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T cell effects and mechanisms in immunotherapy of head and neck tumors

Cell Communication and Signaling volume 21, Article number: 49 (2023) Cite this article

Abstract

Head and neck tumors (HNCs) are a common tumor in otorhinolaryngology head and neck surgery, accounting for 5% of all malignant tumors in the body and are the sixth most common malignant tumor worldwide. In the body, immune cells can recognize, kill, and remove HNCs. T cell-mediated antitumor immune activity is the most important antitumor response in the body. T cells have different effects on tumor cells, among which cytotoxic T cells and helper T cells play a major killing and regulating role. T cells recognize tumor cells, activate themselves, differentiate into effector cells, and activate other mechanisms to induce antitumor effects. In this review, the immune effects and antitumor mechanisms mediated by T cells are systematically described from the perspective of immunology, and the application of new immunotherapy methods related to T cells are discussed, with the objective of providing a theoretical basis for exploring and forming new antitumor treatment strategies.

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Background

Head and neck cancers (HNCs) account for 5% of malignant tumors, and are the sixth most common malignant tumors worldwide, and represent the eighth leading cause of tumor-related deaths [1,2,3,4]. According to the Global Cancer Information Network 2020, there are approximately 800,000 new cases of head and neck cancer worldwide annually, including 450,000 deaths [5]. HNCs is a multifactorial malignancy, traditional tobacco and alcohol have been considered the main risk factors for HNCs [6]. As smoking and HNCs related to smoking have declined in the last 20 years, the proportion of HNCs related to human papillomavirus (HPV) has increased annually [7]. Of the 600,000 cases of HNC worldwide, approximately 8.5 million cases are caused by high-risk HPV infection, making HPV the second most common cause of HNC after smoking [8]. Because HNCs are located in a key position of the upper respiratory tract, surgical treatment of HNCs often significantly compromises patient quality of life by affecting breathing, swallowing, speech, and even appearance [9].Despite recent advances in surgical radiotherapy (RT) and chemotherapy for HNCs, there is still no significant improvement in survival for HNC patients, especially for recurrent/metastatic HNCs (R/M HNCs), with few effective treatment options [10]. Therefore, it is urgent to explore immunotherapy for HNCs. Several studies have shown that the degree of T-cell infiltration in HNCs is closely related to improved prognosis [11,12,13,14,15]. An increase or decrease in the number of T cells in different compartments of the body can promote or inhibit the invasiveness and prognosis of HNCs [16,17,18,19,20]. T cell-related immunotherapy has become the main focus of HNC immunology research [21]. T cell-associated immunotherapy is long-lasting and less toxic than conventional surgery [22] or chemoradiotherapy. Immunological mechanisms based on T cells have produced different forms of immune therapy; the main purpose of these methods is to enhance the immune system response (especially T cells) and to suppress immune checkpoints [23] including tumor vaccines directed against tumor antigens, the use of targeted drugs directly stimulate the immune system, following direct inoculation tumor related to T cells and immune checkpoint therapy.

In this paper, the role of T cells in the treatment of HNCs and the mechanism of immune-mediated effects mediated by T cells were systematically described from the perspective of immunology (Fig. 1), and the application of new immunotherapy methods related to T cells were analyzed, hoping to provide a theoretical basis for exploring and forming new antitumor treatment programs.

Fig. 1
figure 1

HNCs can inhibit t-cell-mediated activation of immune responses through three pathways. 1 Tumor cells can express MHC I molecules on the cell surface and form an antigenic peptide-MHC CLASS I molecular complex through the MHC I pathway, which provides the first signal for T cell activation. CD8+ T cells can initially transform into CTL after receiving the first signal 2 At the same time, tumor cells can recognize MHC class II molecules on the surface of APC cells by pattern recognition receptors (PRR). Some MHC II molecules can form the first signal through cross-presentation and participate in the initial activation of CTL cells through the endogenous antigen presentation pathway. Other MHC CLASS II molecules can form an antigenic peptide-MHC Class II molecular complex through the MHC II pathway to activate CD4+ T cells to produce costimulatory molecules, and at the same time provide a second signal for the activation of CD8+ T cells to fully activate and maintain CTL proliferation and cloning. 3 Tumor cells and APC cells can also secrete costimulatory molecules and participate in the formation of the secondary signal

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The role of T cells in HNCs

T cells play a key role in the specific immunity of HNCs [24]. T cells can directly kill tumor cells and inhibit their proliferation, infiltration, and even tumor metastasis. T cells involved in this activity include CTL and Th cells [25]. However, tumor cells can also actively induce the production of regulatory T cells (Tregs) and other regulatory cells in the host body to resist the antitumor immune response, thus obtaining an environment suitable for proliferation and growth [26].

The killing effect of cytotoxic T cells (CTL) and helper T cells (Th) on HNC cells

Direct killing effect of CTL on HNCs

All nucleated cells express major histocompatibility complex (MHC) class I molecules, and HNCs are no exception [27]. Once T cells detect the antigen peptide-MHC I complex presented by HNCs, CD8+ T cells are activated to form CTLs, thus destroying tumor cells that present target antigens. In mouse experiments, Malik et al. [28] found that CD8+ T cells isolated from vitiligo patients (patients with vitiligo overexpress CD8+ T cells) could be recognized in vitro and trigger apoptosis of mouse melanoma tumor cells [27, 29]. This experiment showed that CTL had a direct killing effect on tumor cells. CTL specifically kills tumor cells through two pathways. The first pathway is the perforin/granzyme pathway [30]. The perforin monomer can be inserted into the target cell membrane, and in the presence of calcium ions [31] multiple perforin can be polymerized into pores with larger inner diameter, so that cytotoxic proteins such as granzyme can quickly enter cells [32]. Backes et al. found in perforin-deficient mouse models that the perforin-granzyme pathway plays a dominant role in mouse and human CTL cells [33]. The second pathway is the Fas-FasL and THF-TNFR pathway or death receptor pathway. CTLs can induce target cell apoptosis by expressing FasL or secreting TNF-α and activating the intracellular signal transduction pathway involving caspases [34].

Killing effect of Th cells on HNCs

Th cells can kill tumor cells in two ways. First, Th can kill tumor cells directly through the cytolysis mechanism [35]. Couture et al. concluded that artificially transferred CD4+ Th in lymphocytopenia mice could not only produce granzyme B with MHCII-dependent cytotoxic activity, but also directly reject melanoma tumors through interferon (IFN)-dependent mechanism [36]. Meanwhile, Th17-polarized T cells can also directly induce tumor cell vascular necrosis by generating the angiogenic factor TNF. Conversely, Th can indirectly enhance the antitumor effect of the body by regulating CTL. Bannard et al. demonstrated that CD4+ T cells, upon recognition of MHCII, modulate antigen presenting cells (APCs) through CD40-CD40L, providing appropriate stimulation for CD8+ T cells to produce a durable immune response to cross-presented antigens on the same APC [37]. Brightman et al. concluded that without the regulatory effect of Th cells on CD8+ T, CTL cells would not be able to effectively produce memory immunity and secondary proliferation, resulting in a durable antitumor effect [38]. Doorduijn et al. [39] and Sato et al. [40]. demonstrated in different mouse experiments that Th cells can recruit and activate monocyte macrophages and CD8+ T lymphocytes through the release of cytokines and chemokines by extracelluar vesicles(EV) and induce an antitumor reaction. IFNγ-induced chemokines can recruit CTL to form an MHC II-dependent tumor-killing effect.

Promoting the effects of regulatory T cells (Treg) on the growth of HNC

Sakaguchi et al. through a several experiments have revealed that in newborn mice thymectomy can inhibit autoimmune T cell activation and limits the associated inflammatory response by providing T cell from thymic mice, these mice achieve an autoimmune response that is dependent on T cells[41]. This experiment demonstrated the existence of a special type of T cells in the thymus that play a negative role in immune regulation [42]. In 2003, the transcription factor FoxP31 specifically expressed in Treg cells was identified in rodents and humans [43], and subsequent experiments demonstrated that FoxP31-mutated Scurfy mice spontaneously develop fatal systemic autoimmune diseases [44]. Therefore, numerous experiments have shown that Treg cells play a key role in maintaining self-tolerance and preventing various autoimmune diseases [45]. Cillo et al. found that CD137high Treg enrichment was associated with poorer overall survival after analysis of 131,224 single-cell transcriptional profiles of HNCs patients and healthy donors[46].In HNCs, Tregs can bind IL-2 released by activated neighboring T cells through highly expressed receptors with high affinity for affinity for IL-2 and secrete inhibitory cytokines IL-10 and TGF-β [47], as well as directly kill effector T cells, thus maintaining immune homeostasis[48]. Early HNC cells often promote Treg production in the host body to inhibit the collective antitumor effect.

Enhanced sensitivity of T cells to HNC chemoradiotherapy

To study the role of T cells in chemotherapy (CRT), Aurelie et al. used HPV-associated squamous cell carcinoma of the head and neck (HNSCC) as a preclinical model. In this study, the CTX and iNOS inhibitor L-NIL was used as a target to analyze differences in the immune response between the two models of radiation therapy and chemotherapy alone and combined therapy with CRT + CTX/L-NIL [49]. Combination therapy improves intratumoral T cell infiltration and tumor antigen specificity of T cells to achieve a better therapeutic effect than chemotherapy alone. The CD8+ T cell/regulatory T cell ratio increased 31.8 times in patients treated with combination immunotherapy compared to CRT alone, and tumor antigen-specific CD8+ T cells increased significantly. These data suggest that reducing intratumor Treg levels or increasing CD8+ T cell infiltration can enhance the antitumor effect of the body [50] and can increase the sensitivity of refractory tumors to CRT, thus improving the immune benefit of CRT [51,52,53].

Several publications have reported that the high correlation between CD8+ tumor-infiltrating lymphocytes (TIL) and CRT may be one of the key factors that mediate the effective response of CRT. Gerber et al. demonstrated that the reduction in the number of CD8+ T cells in the body would reduce the antitumor effect mediated by IFN in RT. Furthermore, chemotherapy could change the tumor microenvironment by releasing tumor antigens and promoting dendritic cell (DC) accumulation, thus improving the antitumor effects of CD8+ T cells[54]. Brakenhoff et al. analyzed the biological signals of 197 HPV-negative (nrgative advanced stage HNSCC) patients with advanced HNSCC before and after radiotherapy and chemotherapy, and the analysis results showed that high CD8+ T profile was closely associated with good prognosis[55].Recent studies have shown that TIL density and PD-L1 expression are correlated with the prognosis of HNC patients. These studies first analyzed the correlation between PD-L1 expression and CD8+ TIL density, and further investigated the relationship between these immune parameters and chemoradiotherapy sensitivity in the primary tumor region and with the prognosis of HNC patients. Studies have shown that patients with HNC with a higher DENSITY of CD8+ TIL have significantly higher disease-free survival or OS [15, 56]. Ono et al. statistically analyzed and recorded TIL density in 106 patients with HNC who received chemoradiotherapy before treatment and found that there was a positive correlation between elevated CD8+ TIL concentration and favorable response to adjuvant chemotherapy in patients with advanced hypopharyngeal cancer [57]. Meanwhile, Maimela et al. found a correlation between increased CD8+ TIL density and reduced distant metastasis of tumor cells and an increased survival rate in a large number of studies [58]. Toshihiko Kawaguchi et al. proposed that in the future, the prognostic effect of CRT in high-risk patients could be determined by assessing the density of CD8+ TIL after pretreatment, and whether adjuvant therapy (additional RT, chemotherapy or immunotherapy) would be required[59].

Immunological mechanism of T cells in HNC therapy

The immunological mechanism of HNCs includes innate immunity and specific immunity mediated by T cells [60]. Innate immunity is the first line of defense against cancer, which includes the direct antitumor effects of NK cells and macrophages. Furthermore, Elmusrati et al. reviewed a large body of literature and concluded that NK cells can further trigger adaptive immune responses by releasing cytokines (IL-2, IL-12, IL-15, IFN-γ, and TNF-α) [61, 62]. However, innate immunity is of limited use against tumors and does not establish long-term immune memory. On the contrary, T-cell-mediated specific immunity plays a key role in this regard. The antitumor effect mediated by T cells in HNCs is the most important mechanism of the antitumor effect in the body (Fig. 2). First, T cells must complete HNC recognition to exert effective immune activity. After complete recognition of HNCs, T cells in the activation process itself, including MHC, provide the first signal to trigger the activation of T cells, and at the same time, of mature APC cells. Th release all kinds of stimulating molecules, thus providing the second signal for activation of T cells, which allows the T cells to fully activate [63]. After complete activation of T cells, a variety of cytokines secreted by APC will continue to participate in the proliferation and differentiation of T cells acting as the third signal required for activation of T cells. Without the participation of such molecules, T cells will undergo apoptosis after activation, and thus interfering and interrupting the overall immune response[64]. After T cells complete their own activation, the antitumor effect mediated by T cells begins formally, and T cells will differentiate into CTL and Th cells to participate in the subsequent immune response.

Fig. 2
figure 2

a Tumor cells express MHC-I molecules to provide the first signal for T cell activation through the MHC-I pathway, leading to initial activation of CD8+ T cells in CTL. b The APC recognizes tumor cells using pattern recognition receptors (PRRs), and then expresses MHC-II molecules and delivers them to CD4+ T cells, activating Th cells. c DCs can cross-present MHC-II molecules to CD8+ T cells through the MHC-I pathway and induce their differentiation into CTL. d APC and Th cells can produce a variety of co-stimulatory molecules, which provide a second signal for T cell activation, which allows T cells to fully activate

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Recognition of HNCs by T cells

Every cell in the body has an identity card that determines whether it is allowed to exist or be eliminated, and the MHC gives cells the ability to be specifically recognized by immune cells. In the human body, MHC is collectively known as the human leukocyte antigen (HLA) complex. HLA is a key component of T cell activation that can present captured tumor antigens (TAs) to T cells [65]. Compared with normal cells, HNCs often achieve immune evasion by downregulating HLA expression, so MHC plays a key role in the immune recognition of HNC cells by T cells [66, 67].

MHC I recognizes T cells on the surface of HNCs cells

HNCs surface expression of MHC I is an important factor in the specific recognition of tumor by T cells.MHC class I molecules are distributed on the surface of all nucleated cells, and they can recognize and present endogenous antigenic peptides, providing the first signal for T cell activation, which can only initially activate T cells. To study the specific relationship between MHC-I and T cells, Agerer et al. found that the stability of the MHC-I peptide on the cell surface of the SARS-COV-2 gene mutation was decreased, so these cells had a certain ability to evade recognition of CTL [68]. The expression of MHC-I is often dysregulated in tumor cells. Yamamoto et al. found that in pancreatic ductal carcinoma (PDAC), the expression of MHC-I was often inhibited by autophagosomes and lysosomes[69], and in autophagy deficient mice, the expression of MHC-I increased in PDAC cells and T cells produced a stronger antitumor effect[68]. Similarly, HNCs often evade immune monitoring by downregulating class I MHC molecules. Yoo et al. analyzed MHC class I expression in 163 patients with HNC, and immunohistochemistry showed that the expression of MHC class I molecules was significantly reduced in approximately 50% of patients' tumors, among which MHC I expression was not detected in 12.7% of patients[70].

T cells are recognized by MHC II presented by APC

Class II molecules are only expressed on the surface of specific cells, such as specialized antigen-presenting cells (B cells, giant cells, DCs), thymic epithelial cells, and activated T cells[71,72,73]. Specialized antigen-presenting cells (APCs) play the most vital role. These cells can recognize and present exogenous antigenic peptides and present them to T lymphocytes in the form of a molecular complex of antigenic peptide-MHC to activate them in Th cells [74,75,76], thus inducing activation and proliferation of CD8+ T cells[77]. The recognition function of APC depends on a special receptor expressed on its surface, namely the pattern recognition receptor (PRR). PRRs recognize conserved repetitive gene sequences in microbial species, known as pathogen-associated molecular patterns (PAMPs), and enable APCs to distinguish between themselves, that is, non-self cells and even tumor cells with abnormal gene expression [78, 79]. APC constitutively expresses MHC class II costimulatory molecules and adhesion molecules, which provide initiation signals for T cell activation. The presence of APC provides a powerful aid for tumor antigen presentation and T cell activation.

Self-activation of T cells in HNCs

After initial recognition of the tumor antigen, T cells need their own activation to produce the antitumor effect. T cell activation needs to receive two types of signals, among which CD8+ T cells specifically recognize MHC-I molecules bound on the surface of HNC. After receiving the first signal, CD8+ T cells activate transcription factors to cause the transcription of various membrane molecules and molecular genes related to cell activation, so they are initially activated as CTL cells. At the same time, APC in contact with T cells are also activated, and MHC-II molecules are presented to CD4+ T cells through the MHC-II pathway to activate Th cells and generate costimulatory molecules to provide a second signal for complete activation of CTL cells.

T cells form preliminary activation through the first signal

Specific binding of the T cell antigen receptor (TCR) on the surface of T cells in HNCs and pMHC presented by APC is called antigen recognition, through which T cells initiate their initial activation [80]. Antigen recognition follows MHC restriction, that is, TCR must recognize its own MHC molecules in the pMHC complex while specifically recognizing the antigenic peptides presented by APC. The restriction of MHC restriction determines that any T cell recognizes only the pMHC presented by APC of the same individual. This restriction is determined by the CD4 and CD8 receptors on the surface of T cells. As co-receptors of TCR, CD4+ or CD8+ cells can recognize MHC-II molecules on the surface of tumor cells or APC [71], respectively, and these two molecules can act as the first signal of T cell activation to activate T cells through the MHC-I pathway. CD8+ T specifically recognizes MHC-I on the surface of tumor cells through the MHC-I pathway and is initially activated in cytotoxic T cells (TCL) with a certain activity [81], which is an endogenous recognition pathway that can occur in all nucleated cells. Although the MHC-I pathway only targets endogenous antigens, there is a cross-presenting antigen presentation pathway that can load MHC-II molecules from the exogenous antigen-activated MHC-II pathway into the endogenous MHC-I pathway [82]. This latter pathway plays a key role in antimicrobial and antitumor immunity and immune tolerance [83].

T cells complete activation through a second signal

T cells cannot perform tumor clearing without the presence of the second signal.Lafferty et al. found that foreign tissues depleted of white blood cells could not induce an immune response. Furthermore, in the absence of cells that present antigens or immobilized antigens, stimulation of T cells to neither to clonal expansion nor to the production of the IL-2 required to maintain T cell proliferation, leading to the conclusion that T cell activation requires a second signal in addition to the first signal [84]. Meissner et al. compared MHC class II antigen processing machinery (APM) expression in HNCs cell lines (cancer lesions) with interferon (IFN)-gamma-regulated expression profiles and found that there was a lack of constitutive MHC II surface expression in head and neck cancer cellsm[71].Gameiro et al. found that the significant increase in the expression of the MHC II gene was strongly associated with a significant up-regulation of genes for various costimulatory molecules of T cells required for T cell activation and survival after TCGA of more than 500 HNCs [85]. At the same time, Axelrod et al. summarized a large number of studies and concluded that CD4+ T cells can recognize MHC-II and activate them to proliferate as helper T cells (Th) and express the corresponding cytokines involved in the activation of T cells [73]. Homet et al. treated melanin mice with anti-PD-1 and found that recovery of the CTL response required the participation of mouse CD4+ T cells [86]. Meanwhile, Laidlaw et al. concluded that CD8+ T cells could not produce an effective and lasting memory response without the help of CD4+ T cells [87]. Therefore, co-stimulatory molecules with immune-regulating effects can be used as a second signal to participate in complete activation of T cells and to maintain the proliferation and cloning of CTL cells, and MHC-II and CD4+ T cells must be involved in this process.

T cells are activated by dual signals provided by DC cells.

Dendritic cells(DC) are very important targets in HNCs immunotherapy. Abolhalaj et al. compared the frequency of DCs in a large number of benign tonsil tissues with that in malignant tonsil tissues. The results showed that the frequency of DCs, the expression of immune molecules and the level of genes involved in immune response were lower in the malignant tonsil group[88].DCs are the most powerful APCs with many maturing dendritic processes, which can recognize, absorb and process exogenous antigens and present antigenic peptides to primary T cells to induce activation and proliferation of T cells [89, 90]. Among APCs, DCs are the only specialized APCs that can capture and process tumor antigens and directly activate primary T cells [91]. DCs provide primary and secondary signals for T cell activation [92]. Immature DCs recognize tumor antigens through PRRs and induce DC maturation and proliferation [92]. Mature DCs present MHC II molecules to CD8+ T cells through cross-presenting [93]. An antigenic stimulus signal (the first signal) that provides initial T cell activation leads to initial T cell activation into CTLs [94]. At the same time, mature DC cells also release multiple exosomes of secretory or paracrine cytokines (second signal) exosomes, which further bind and induce the proliferation and differentiation of activated T cells, thus triggering the initial immune response. In addition, DCs have a certain immunomodulatory effect. DCs secrete a large amount of IL-I2 to induce primary T cells (Th0) that differentiate into Th1 cells and produce the immune response Th1 cell. However, it is not clear how cross-presenting allows CD8+ T cells to activate recognition of all antigenic peptides presented by exogenous cells. DC cells are excellent mediators, which can recognize tumor antigens and present two signals required for T cell activation at the same time. Therefore, HNCs tumor vaccine prepared based on DC cells has been widely used in clinic.

T cell-mediated adaptive immune mechanism of HNCs

Schumacher et al. reviewed a large number of studies and concluded that tumor cells have different antigen components from normal tissue cells, and it is by recognizing these antigens that T cells form specific killing effects on tumor cells [81]. Tumor cells can escape normal immune monitoring because most are weakly immunogenic, and it is difficult for the body to induce a specific immune responses to these antigens. However, as an existing immune mechanism in the body, artificially inducing and activating this pathway to recognize and kill tumor cells is a means of immunity with the least damage to the body. Among them, tumor immunotherapy related to T cells has become the focus of immunotherapy.

T cells are induced to differentiate into cytotoxic T cells to kill HNC cells

CTL is a key component of antitumor immunity [95]. A large amount of evidence showed that the depth of CTL infiltration in the body was closely related to the prognosis of HNCsS [15, 19, 96]. Apoptotic or necrotic tumor cells release antigens, which are processed by APC, including DC, and present MHC to TCR receptors in CD8+ T cells. When the tumor releases a large number of highly expressed costimulatory molecules of EVs, APCs or DCs can directly present the antigen to CD8+ T cells[97], stimulate their synthesis of IL-2 and proliferation and differentiation into CTL with a specific killing effect on tumor cells. CTL specifically kills target cells by recognizing pMHC-I presented by target cells. However, HNCs often avoid CTL recognition by reducing the expression of MHC I, thus forming immune evasion. The killing mechanism of CTL on tumor cell. includes the following two pathways: one is the perforin/granzyme pathway and the other is the death receptor pathway [98]. Stimulation of CTL initiation is mediated in the form of cytokines secreted by CD4+ Th cells [99]. CD4+ T cells interact with antigens in the MHC-II molecular pathway and secrete cytokines to help CTL proliferation and activation. Therefore, when the tumor does not express or has a low expression of costimulatory molecules, the activation of CD8+ T cells also requires the help of activated CD4+ Th cells [25]. CTL's killing of HNCs depends on a variety of activation signals. However, tumor cells often reduce or inhibit the expression of relevant activation signals to avoid CTL's killing. At present, most T cell-related immunotherapy aims to up-regulate relevant activation signals to enhance the killing and recognition ability of CTL cells to tumors.

T cells induce differentiation into Th cells to regulate the killing effect of CTL HNCs

In mice, CD4+ Th1 cells play an important auxiliary role in the activation of CD8+ CTL [100]. When the body has low expression of costimulatory molecules, these can be secreted by Th cells to activate CD8+ T cells. While inducing CTL differentiation, some CD4+ Th1 cells also have the ability to kill tumor cells directly [101]. To date, the role of CD4+ Th in HNCs immunotherapy is obviously neglected. The immune response of T cells is always suboptimal without the help of CD4+ Th cells [102]. However, the exact role of Th cells in HNCs remains unclear [19]. There is still a gap in Th cell related HNCs immunotherapy.

Immunotherapy of HNCs associated with T cells

Many of the difficulties in studying and treating HNCs are that HNCs are a heterogeneous group of cancers of different anatomical structures, are highly immunosuppressive [103], are associated with different risk factors, and have different molecular pathology. Despite current state-of-the-art treatments, the recurrence rate of HNCs remains unacceptably high [104]. In fact, 65% of HNCs recur [105], and in these cases, the 5-year survival rate for patients with advanced HNC is only 35% to 45% [106, 107]. To eliminate this adverse outcome, the treatment of HNCs has begun to adopt immunotherapy strategies [108]. T lymphocytes as the main antitumor cells, most tumor immunotherapy methods seek to expand cytotoxic T lymphocytes targeting malignant cells [30]. Currently, antitumor vaccines, targeted drugs, immune checkpoint inhibitors, and other therapies have been widely used in HNC immunotherapy (Table 1).

Table 1 Progress in immunotherapy protocols for HNCs
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Specific immune effects of tumor vaccine-activated T cells on HNCs

Tumor vaccines are an immune-mediated therapy aimed at inducing an antitumor immune response by injecting immunogenic tumor vaccine into the host. This is a targeted immunotherapy. Currently, protein polypeptide vaccines, gene modified vaccines, and DC vaccines have the most developed. Cancer vaccines are designed to activate T cells to generate an adaptive immune system by presenting the tumor antigen TSA or TAA via APC. TSA-specific vaccines are preferred because the antigen will be specific to tumor cells, thereby avoiding an autoimmune response to normal cells [114]. TSA-targeted vaccines may be suitable for only a small subset of HNCs because HNCs, particularly HPV-negative HNCs, have a high mutation rate [115]. DC cells have unique functions in absorbing tumor antigens and activating T cells to produce antitumor effects, so the DC vaccine is a very potential tumor vaccine therapy among many vaccines [89]. Gross et al. have shown that DC vaccines are safe for several types of cancer and have been shown in clinical trials to induce long-lasting T cell responses[116]. Schuler et al. and Whiteside et al. tested toxicity and efficacy in HNC patients using peptides synthesized from autologous DCS in vitro or vaccines loaded with tumor protegens or tumor cells. They found that these drugs were not toxic, but the preparation was laborious and, despite repeated use in patients with advanced HNC, most were ineffective [109, 110]. Whiteside et al. concluded that tumor vaccine inoculation for HNCS patients could produce a certain immune effect on the body, but the therapeutic effect on the tumor was still not obvious. In a word, tumor vaccine can be used as an auxiliary means in the combination of HNCS and preventive therapy, which can effectively stabilize TME, provide a good environment for other treatments, and prevent tumor recurrence to a certain extent[117].

Antitumor effects of T cells induced by targeted drugs

Cetuximab is one of the best targeted drugs for head and neck tumors, and its main antitumor effect is attributed to the blocking of EGFR signal[118].Gildener-Leapman et al. found that epidermal growth factor (EGFR) was overexpressed in 80%-90% of HNC cases, resulting in excessive proliferation, invasion, and angiogenesis of tumor cells [119]. Cetuximab is a monoclonal antibody of chimeric immunoglobulin G1 (IgG1) [120] that competently inhibits ligand binding to EGFR and induces immune function. For example, activation of the FC receptor FCgRIIIa on the surface of NK cells induces ADC, or cross-activation of DCs and NK stimulates cytotoxic T cells to form an antitumor response [121].

The landmark EXTREME trial, published in 2008, evaluated cetuximab in 442 patients with HNC. The results showed a median survival increase of 2.7 months in the cetuximab group compared to those treated with chemotherapy alone [111]. Cetuximab was approved by the US FDA in November 2011 for the first-line treatment of R/M HNC [122]. In 2006, Bonner et al., in a study evaluating advanced local HNCs, found that adding cetuximab to RT could improve the local control rate of tumors and could significantly improve OS [123]. Gillison and Gebre et al., through subsequent phase II and III studies, showed that cisplatin combined with RT is superior to cetuximab plus RT in the local control of HNCs and improvement of OS [124, 125]. Mehanna et al. conducted an open-label randomized controlled Phase 3 trial on patients with low-risk papillomavirus-positive oropharyngeal cancer, and found that cetuximab showed no advantage in reducing drug toxicity and improving patient survival compared with cisplatin protocols. And there is some damage to tumor control[126]. There is increasing evidence that cetuximab alone is not a recommended strategy for treating head and neck tumors.Today, cetuximab is often used in combination with chemoradiotherapy and immune checkpoint inhibitors, which provides a direction for future combination immunotherapy [127,128,129].

T cells can be used directly as immunotherapy drugs for HNCs: CAR-T

T cells amplified and activated in vitro, including cytokine-induced killer cells (CIK), TIL, and tumor antigen-specific CTL, can also be adopted into the tumor-bearing host. The most important achievement in this regard has been modified T cells based on chimeric antigen receptor (CAR) (CAR-T) [130]. In CAR T cell therapy, genetically engineered autologous T cells expressing CAR are used in patients. CAR binds antigens independently of MHC and is therefore immune to downregulation of MHC of tumor cells, which is an effective means of avoiding immune evasion by malignant tumor cells [131]. However, this approach has obvious defects, that is, side effects caused by cytokine release lead to life-threatening immune overactivation and neurotoxicity, and the treatment effect of this therapy in solid tumors is not satisfactory [132, 133]. In the treatment of HNCs, several CAR T cells targeting different antigens have been developed and entered clinical trials, including ErbB, HER2, MUC1, LMP1, NKG2D, etc. One of the attractive antigens is the ErbB family, which consists of four members called epidermal growth factor receptors EGFR or erBB-1, erBB-2, erBB-3, erBB-4. Larcombe-Young et al. found that dysregulation of ErbB signaling was common in the pathogenesis of HNCS, and EGFR was strongly overexpressed in 90% of the cases[134]. However, targeted therapy for EGFR is often influenced by members of the ErbB family, leading to a poor prognosis. Pan-targeted ErbB T4 + CAR therapy for these conditions has entered clinical trials. CAR + T4 was specific against all EGFR homologous ErbB antigens simultaneously. In this way, T cells obtained strong cytotoxic activity against multiple tumor types, reducing the impact of homologous tumor-associated antigens on CAR-T therapy. Meanwhile, a safety clinical trial of T4 treatment in HNCS patients (NCT01818323) showed that no cytotoxic events occurred in the majority of patients receiving T4 continuous treatment[135]. However, the treatment of CAR-T in head and neck tumors still faces challenges such as the transport and osmosis of CAR-expressed T cells into the tumor microenvironment of malignant deposition, malignant inflammation, hypoxia, and metabolic dysfunction[60]. Therefore, it is not difficult to find that CAR-T therapy depends on the tightly controlled tumor microenvironment, which may give CAR-T therapy in combination therapy mode and may show better efficacy.

Examination of immune checkpoint inhibitors to improve the immune effect of T cells on HNCs

Removal of the immunosuppressive state of tumor patients to treat tumors is the biggest breakthrough in the theory and application of tumor immunotherapy; the most prominent progress is immune checkpoint therapy. Immune checkpoint molecules are a class of immunosuppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and Programmed death protein 1 (PD-1) [136], which are inhibitory costimulatory molecules that act after activation of T lymphocytes and persist in the presence of stimulus. Pd-1 is often seen as a "depletion marker" whose stimulation induces the formation of impotent T cells [137]. These cells do not express adjuvant (CD4+) or cytotoxic (CD8+) activity against tumor cells [138]. Zandberg and Strome et al. evaluated PD-1 staining results of HNCs (mainly oropharyngeal tumors) and showed that approximately half of oropharyngeal squamous cell carcinomas (OSCCs) expressed PD-L1 [139]. A higher expression of PD-1 was identified in HPV(+) tumors. Immune checkpoint therapy is a therapeutic strategy that modulates T cell activity to improve the tumor immune response by targeting co-inhibitory or co-stimulating signals. PD-1 and CTLA-4 are thought to be marker genes for depleted CD8+ T cells [140]. The study of CTLA-4 and PD-1 and its PD-1 ligand is considered a milestone event in immunotherapy.

In 2016, nivolumab and pembrolizumab, two anti-PD-1 antibodies, were shown to improve survival (OS) in patients with relapsed metastatic HNC and were approved by the US Food and Drug Administration (FDA) for second-line therapy [141]. This provides a new standard of care for R/M HNCs. Compared to standard cytotoxic chemotherapy, immunotherapy improves patient survival through a durable response [142]. Although this is an encouraging development, several studies have shown that while the PD-1/PD-L1 inhibitor in HNC immunotherapy can increase the response rate from 13 to 20%, survival (OS) improves in only 1 in 10 patients. This statistical result may indicate that few patients with HNC respond to immune checkpoint therapy[143], but that a certain percentage of patients will have lasting benefits [112].

Combination immunotherapy associated with T cells in HNCs

David et al.'s Version 2.2020, NCCN Clinical Practice Guidelines in Oncology indicate that the current preferred nonsurgical treatment for HNCs is platinum-based dual chemotherapy (mainly cisplatin and carboplatin) [144]. Refractory and metastatic HNCs are often targeted with drugs such as cetuximab, methotrexate, and taxanes, all of which have significant side effects and a low response rate of only 10–13% [145]. Chemotherapy in HNC patients tends to be temporary, does not significantly extend life expectancy, and rarely prevents most patients from dying of malignancy [146]. Based on the above conclusions, it is not difficult to find that the efficacy of antiviral drugs alone for patients with HNC is limited. Therefore, international research on immunocombination therapy is increasing, that is, the combination of a novel immune modulator with PD1/PD-L1 inhibitors [147]. Chemotherapeutic agents are logical partners of ICIs in HNC. ICIs improve cytotoxic T cells and promote tumor regression and immune rejection. Targeted drugs can induce antibody-dependent cytotoxicity (ADC) and cause immune cells to talk to each other, including NK cells and DCs. This mutually reinforcing immune effect can initiate tumor antigen-specific cellular immunity and enhance the antigen-specific T-cell response [148].

Multiple trials have also shown that multimodal combinations of treatments have better response rates than conventional therapies alone[113]. Burtness et al. reported that pembrolizumab combined with platinum and 5-fluorouracil significantly improved OS in 882 patients with locally untreatable recurrent or metastatic HNC treated at 200 centers in 37 countries, compared to cetuximab plus platinum and 5-fluorouracil alone [149]. In 33 patients with platinum-resistant recurrent or metastatic HNC (platinum-resistant, recurrence, or metastatic HNCs), Sacco et al. demonstrated that pembrolizumab combined with cetuximab could achieve an overall response rate of 45%. This exceeds the published response rates for pembrolizumab (16–18%) or cetuximab (6–13%). Furthermore, the overall response rate was consistent with that of pembrolizumab combined with platinum bivalent chemotherapy (36–43%) in Burtaness et al. Effective evaluation of the large number of immune combinations in HNC still requires more innovative experimental design and analysis of the biomarkers of the serum [150]. We can foresee the development and introduction of HNCs immunotherapy in the future as a powerful complement to traditional therapies (surgery, RT, and chemotherapy).

HNCS often have a complex tumor microenvironment, and single immunotherapy is often affected by a variety of unpredictable factors, including inflammation, hypoxia and metabolic disorders in the tumor microenvironment. Combination therapy can ensure that the tumor is in a stable or even beneficial state of immune effect of immune drugs in many aspects, and there are even complementary effects between multiple drugs. We can foresee the development and introduction of HNCs immunotherapy in the near future, which is expected to be a powerful complement to traditional therapies (surgery, RT and chemotherapy).

Conclusions

Traditional surgical treatment has significant detrimental impact on the quality of life of HNC patients, while for R/M HNC patients, the effect of traditional surgical treatment and radiation therapy and chemotherapy is poor and often cannot significantly improve the survival rate of patients. Therefore, immunotherapy is necessary for HNC patients. Several studies have shown that T cells are the main antitumor cells. However, HNCs can reduce MHC expression in many ways to avoid recognition and killing of T cells. Therefore, how to inhibit immune escape from tumor cells or improve the immune effect of T cells on tumor cells is now the focus of immunotherapy research. Understanding and clarifying the mechanism of T cells with antitumor activity in the body can be targeted to develop relevant immunological treatment methods. However, in HNC immunotherapy, the effect of single immunotherapy is not ideal and is characterized by two concurrent problems: an exceptionally low response rate and a remarkably high recurrence rate. The emergence of combined immunotherapy provides a new direction and hope for HNC immunotherapy. Especially combination immunotherapy of ICIs and targeted drugs theoretically should induce synergistic effects and the efficacy of this combination has been evidenced in clinical trials.

Availability of data and materials

Not applicable.

Abbreviations

HNCs:

Head and neck tumors

CTL:

Cytotoxic T cells

Th:

Helper T cells

ICI:

Immune checkpoint inhibitor

HPV:

Human papillomavirus

R/M HNCs:

Recurrent/metastatic head and neck tumors

RT:

Radiotherapy

Tregs:

Regulatory T cells

APCs:

Antigen presenting cells

EV:

Extracelluar vesicles

CRT:

Chemotherapy

TIL:

Tumor-infiltrating lymphocytes

DC:

Dendritic cell

HLA:

Human leukocyte antigen

TAs:

Tumor antigens

PDAC:

Pancreatic ductal carcinoma

PRR:

Pattern recognition receptor

PAMPs:

Pathogen-associated molecular patterns

TCR:

T cell antigen receptor

EGFR:

Epidermal growth factor

CIK:

Cytokine-induced killer cells

CTLA-4:

Lymphocyte-associated protein 4

OSCCs:

Oropharyngeal squamous cell carcinomas

ADC:

Antibody-dependent cytotoxicity

NK:

Natural killer

TSA:

Tumor specific antigens

TAA:

Tumor-associated antigens

IL:

Interleukin

IFN:

Interferon

TNF:

Tumor necrosis factor

CAR-T:

Chimeric antigen receptor T cells

PD1:

Programmed cell death 1

PD-L1:

Programmed death-ligand 1

References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53.

    Article  CAS  PubMed  Google Scholar 

  2. Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F, et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin. 2017;67(1):51–64.

    Article  PubMed  Google Scholar 

  3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  4. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  PubMed  Google Scholar 

  5. Cohen N, Fedewa S, Chen AY. Epidemiology and demographics of the head and neck cancer population. Oral Maxillofac Surg Clin North Am. 2018;30(4):381–95.

    Article  PubMed  Google Scholar 

  6. Saiz ML, Rocha-Perugini V, Sánchez-Madrid F. Tetraspanins as organizers of antigen-presenting cell function. Front Immunol. 2018;9:1074.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Poropatich K, Hernandez D, Fontanarosa J, Brown K, Woloschak G, Paintal A, et al. Peritumoral cuffing by T-cell tumor-infiltrating lymphocytes distinguishes HPV-related oropharyngeal squamous cell carcinoma from oral cavity squamous cell carcinoma. J Oral Pathol Med. 2017;46(10):972–8.

    CAS  PubMed  Google Scholar 

  8. Young D, Xiao CC, Murphy B, Moore M, Fakhry C, Day TA. Increase in head and neck cancer in younger patients due to human papillomavirus (HPV). Oral Oncol. 2015;51(8):727–30.

    Article  PubMed  Google Scholar 

  9. Loyo M, Li RJ, Bettegowda C, Pickering CR, Frederick MJ, Myers JN, et al. Lessons learned from next-generation sequencing in head and neck cancer. Head Neck. 2013;35(3):454–63.

    Article  PubMed  Google Scholar 

  10. Buchwald ZS, Schmitt NC. Immunotherapeutic strategies for head and neck cancer. Otolaryngol Clin North Am. 2021;54(4):729–42.

    Article  PubMed  Google Scholar 

  11. Fang J, Li X, Ma D, Liu X, Chen Y, Wang Y, et al. Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma. BMC Cancer. 2017;17(1):375.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dhodapkar MV, Dhodapkar KM. Tissue-resident memory-like T cells in tumor immunity: clinical implications. Semin Immunol. 2020;49: 101415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells. Immunol Cell Biol. 2018;96(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  14. Donnem T, Kilvaer TK, Andersen S, Richardsen E, Paulsen EE, Hald SM, et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol. 2016;27(2):225–32.

    Article  CAS  PubMed  Google Scholar 

  15. Nguyen N, Bellile E, Thomas D, McHugh J, Rozek L, Virani S, et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck. 2016;38(7):1074–84.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Alves AM, Diel LF, Lamers ML. Macrophages and prognosis of oral squamous cell carcinoma: a systematic review. J Oral Pathol Med. 2018;47(5):460–7.

    Article  PubMed  Google Scholar 

  17. Hanna GJ, Liu H, Jones RE, Bacay AF, Lizotte PH, Ivanova EV, et al. Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2017;67:61–9.

    Article  CAS  PubMed  Google Scholar 

  18. Rossa C, D’Silva NJ. Non-murine models to investigate tumor-immune interactions in head and neck cancer. Oncogene. 2019;38(25):4902–14.

    Article  CAS  PubMed  Google Scholar 

  19. de Ruiter EJ, Ooft ML, Devriese LA, Willems SM. The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. Oncoimmunology. 2017;6(11): e1356148.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Balermpas P, Rödel F, Rödel C, Krause M, Linge A, Lohaus F, et al. CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: a multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG). Int J Cancer. 2016;138(1):171–81.

    Article  CAS  PubMed  Google Scholar 

  21. Horton JD, Knochelmann HM, Day TA, Paulos CM, Neskey DM. Immune evasion by head and neck cancer: foundations for combination therapy. Trends Cancer. 2019;5(4):208–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer. 2019;7(1):184.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bolon B, Aeffner F. A primer for oncoimmunology (immunooncology). Toxicol Pathol. 2017;45(5):584–8.

    Article  CAS  PubMed  Google Scholar 

  24. Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359–67.

    Article  CAS  PubMed  Google Scholar 

  25. Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234(6):8509–21.

    Article  CAS  PubMed  Google Scholar 

  26. Qianmei Y, Zehong S, Guang W, Hui L, Lian G. Recent advances in the role of Th17/Treg cells in tumor immunity and tumor therapy. Immunol Res. 2021;69(5):398–414.

    Article  PubMed  Google Scholar 

  27. Zeng Z, Chew HY, Cruz JG, Leggatt GR, Wells JW. investigating T cell immunity in cancer: achievements and prospects. Int J Mol Sci. 2021;22(6):2907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Malik BT, Byrne KT, Vella JL, Zhang P, Shabaneh TB, Steinberg SM, et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci Immunol. 2017;2(10):eaam6346.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mami-Chouaib F, Blanc C, Corgnac S, Hans S, Malenica I, Granier C, et al. Resident memory T cells, critical components in tumor immunology. J Immunother Cancer. 2018;6(1):87.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kaschek L, Zöphel S, Knörck A, Hoth M. A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity. Semin Cell Dev Biol. 2021;115:10–8.

    Article  CAS  PubMed  Google Scholar 

  32. Qu B, Pattu V, Junker C, Schwarz EC, Bhat SS, Kummerow C, et al. Docking of lytic granules at the immunological synapse in human CTL requires Vti1b-dependent pairing with CD3 endosomes. J Immunol. 2011;186(12):6894–904.

    Article  CAS  PubMed  Google Scholar 

  33. Backes CS, Friedmann KS, Mang S, Knörck A, Hoth M, Kummerow C. Natural killer cells induce distinct modes of cancer cell death: discrimination, quantification, and modulation of apoptosis, necrosis, and mixed forms. J Biol Chem. 2018;293(42):16348–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hassin D, Garber OG, Meiraz A, Schiffenbauer YS, Berke G. Cytotoxic T lymphocyte perforin and fas ligand working in concert even when fas ligand lytic action is still not detectable. Immunology. 2011;133(2):190–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W. CD4 + T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635–47.

    Article  CAS  PubMed  Google Scholar 

  36. Couture A, Garnier A, Docagne F, Boyer O, Vivien D, Le-Mauff B, et al. HLA-class II artificial antigen presenting cells in CD4 + T cell-based immunotherapy. Front Immunol. 2019;10:1081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bannard O, Cyster JG. Germinal centers: programmed for affinity maturation and antibody diversification. Curr Opin Immunol. 2017;45:21–30.

    Article  CAS  PubMed  Google Scholar 

  38. Brightman SE, Naradikian MS, Miller AM, Schoenberger SP. Harnessing neoantigen specific CD4 T cells for cancer immunotherapy. J Leukoc Biol. 2020;107(4):625–33.

    Article  CAS  PubMed  Google Scholar 

  39. Doorduijn EM, Sluijter M, Salvatori DC, Silvestri S, Maas S, Arens R, et al. CD4+ T cell and NK cell interplay key to regression of MHC class I low tumors upon TLR7/8 agonist therapy. Cancer Immunol Res. 2017;5(8):642–53.

    Article  CAS  PubMed  Google Scholar 

  40. Sato Y, Bolzenius JK, Eteleeb AM, Su X, Maher CA, Sehn JK, et al. CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade. JCI Insight. 2018;3(23): 121062.

    Article  PubMed  Google Scholar 

  41. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol. 2020;26(38):541–66.

    Article  Google Scholar 

  42. Eggenhuizen PJ, Ng BH, Ooi JD. Treg enhancing therapies to treat autoimmune diseases. Int J Mol Sci. 2020;21(19):E7015.

    Article  Google Scholar 

  43. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4(4):337–42.

    Article  CAS  PubMed  Google Scholar 

  44. Godfrey VL, Wilkinson JE, Rinchik EM, Russell LB. Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci U S A. 1991;88(13):5528–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Basu A, Ramamoorthi G, Albert G, Gallen C, Beyer A, Snyder C, et al. Differentiation and regulation of TH cells: a balancing act for cancer immunotherapy. Front Immunol. 2021;12: 669474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cillo AR, Kürten CHL, Tabib T, Qi Z, Onkar S, Wang T, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity. 2020;52(1):183-199.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee GR. The balance of Th17 versus treg cells in autoimmunity. Int J Mol Sci. 2018;19(3):E730.

    Article  Google Scholar 

  49. Hanoteau A, Newton JM, Krupar R, Huang C, Liu HC, Gaspero A, et al. Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy. J Immunother Cancer. 2019;7(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Jayaraman P, Alfarano MG, Svider PF, Parikh F, Lu G, Kidwai S, et al. iNOS expression in CD4+ T cells limits Treg induction by repressing TGFβ1: combined iNOS inhibition and Treg depletion unmask endogenous antitumor immunity. Clin Cancer Res. 2014;20(24):6439–51.

    Article  CAS  PubMed  Google Scholar 

  51. Rahir G, Wathelet N, Hanoteau A, Henin C, Oldenhove G, Galuppo A, et al. Cyclophosphamide treatment induces rejection of established P815 mastocytoma by enhancing CD4 priming and intratumoral infiltration of P1E/H-2K(d) -specific CD8+ T cells. Int J Cancer. 2014;134(12):2841–52.

    Article  CAS  PubMed  Google Scholar 

  52. Hanoteau A, Henin C, Svec D, Bisilliat Donnet C, Denanglaire S, Colau D, et al. Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8+ T cells. Oncoimmunology. 2017;6(8): e1318234.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Scurr M, Pembroke T, Bloom A, Roberts D, Thomson A, Smart K, et al. Low-dose cyclophosphamide induces antitumor T-cell responses, which associate with survival in metastatic colorectal cancer. Clin Cancer Res. 2017;23(22):6771–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gerber SA, Sedlacek AL, Cron KR, Murphy SP, Frelinger JG, Lord EM. IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor. Am J Pathol. 2013;182(6):2345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van der Heijden M, Essers PBM, de Jong MC, de Roest RH, Sanduleanu S, Verhagen CVM, et al. Biological determinants of chemo-radiotherapy response in HPV-negative head and neck cancer: a multicentric external validation. Front Oncol. 2019;9:1470.

    Article  PubMed  Google Scholar 

  56. Balermpas P, Rödel F, Krause M, Linge A, Lohaus F, Baumann M, et al. The PD-1/PD-L1 axis and human papilloma virus in patients with head and neck cancer after adjuvant chemoradiotherapy: a multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG). Int J Cancer. 2017;141(3):594–603.

    Article  CAS  PubMed  Google Scholar 

  57. Ono T, Azuma K, Kawahara A, Akiba J, Kakuma T, Chitose S, et al. Pre-treatment CD8+ tumour-infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma. Clin Otolaryngol. 2018;43(5):1312–20.

    Article  CAS  PubMed  Google Scholar 

  58. Maimela NR, Liu S, Zhang Y. Fates of CD8+ T cells in tumor microenvironment. Comput Struct Biotechnol J. 2019;17:1–13.

    Article  CAS  PubMed  Google Scholar 

  59. Kawaguchi T, Ono T, Sato F, Kawahara A, Kakuma T, Akiba J, et al. CD8+ T cell infiltration predicts chemoradiosensitivity in nasopharyngeal or oropharyngeal cancer. Laryngoscope. 2021;131(4):E1179–89.

    Article  CAS  PubMed  Google Scholar 

  60. Sim F, Leidner R, Bell RB. Immunotherapy for head and neck cancer. Hematol Oncol Clin North Am. 2019;33(2):301–21.

    Article  PubMed  Google Scholar 

  61. Elmusrati A, Wang J, Wang CY. Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma. Int J Oral Sci. 2021;13(1):24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Santos EM, Rodrigues de Matos F, Freitas de Morais E, Galvão HC, de Almeida FR. Evaluation of Cd8+ and natural killer cells defense in oral and oropharyngeal squamous cell carcinoma. J Craniomaxillofac Surg. 2019;47(4):676–81.

    Article  PubMed  Google Scholar 

  63. Yang S, Wei W, Zhao Q. B7–H3, a checkpoint molecule, as a target for cancer immunotherapy. Int J Biol Sci. 2020;16(11):1767–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Webb GJ, Hirschfield GM, Lane PJL. OX40, OX40L and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2016;50(3):312–32.

    Article  CAS  PubMed  Google Scholar 

  65. Moy JD, Moskovitz JM, Ferris RL. Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma. Eur J Cancer. 2017;76:152–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen SMY, Krinsky AL, Woolaver RA, Wang X, Chen Z, Wang JH. Tumor immune microenvironment in head and neck cancers. Mol Carcinog. 2020;59(7):766–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sun Z, Sun X, Chen Z, Du J, Wu Y. Head and neck squamous cell carcinoma: risk factors, molecular alterations, immunology and peptide vaccines. Int J Pept Res Ther. 2022;28(1):19.

    Article  CAS  PubMed  Google Scholar 

  68. Agerer B, Koblischke M, Gudipati V, Montaño-Gutierrez LF, Smyth M, Popa A, et al. SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses. Sci Immunol. 2021;6(57):eabg6461.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;581(7806):100–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yoo SH, Keam B, Ock CY, Kim S, Han B, Kim JW, et al. Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients. Sci Rep. 2019;9(1):7680.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Meissner M, Whiteside TL, van Kuik-Romein P, Valesky EM, van den Elsen PJ, Kaufmann R, et al. Loss of interferon-gamma inducibility of the MHC class II antigen processing pathway in head and neck cancer: evidence for post-transcriptional as well as epigenetic regulation. Br J Dermatol. 2008;158(5):930–40.

    Article  CAS  PubMed  Google Scholar 

  72. Reith W, Mach B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol. 2001;19:331–73.

    Article  CAS  PubMed  Google Scholar 

  73. Axelrod ML, Cook RS, Johnson DB, Balko JM. Biological consequences of MHC-II expression by tumor cells in cancer. Clin Cancer Res. 2019;25(8):2392–402.

    Article  CAS  PubMed  Google Scholar 

  74. Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15(4):203–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhou P, Liu S, Ji NN, Zhang S, Wang P, Lin B, et al. Association between variant alleles of major histocompatibility complex class II regulatory genes and nasopharyngeal carcinoma susceptibility. Eur J Cancer Prev. 2020;29(6):531–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Spector ME, Bellile E, Amlani L, Zarins K, Smith J, Brenner JC, et al. Prognostic value of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg. 2019;145(11):1012–9.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ecsedi M, McAfee MS, Chapuis AG. The anticancer potential of T cell receptor-engineered T cells. Trends Cancer. 2021;7(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  78. Teixeira RM, Ferreira MA, Raimundo GAS, Loriato VAP, Reis PAB, Fontes EPB. Virus perception at the cell surface: revisiting the roles of receptor-like kinases as viral pattern recognition receptors. Mol Plant Pathol. 2019;20(9):1196–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shekarian T, Valsesia-Wittmann S, Brody J, Michallet MC, Depil S, Caux C, et al. Pattern recognition receptors: immune targets to enhance cancer immunotherapy. Ann Oncol. 2017;28(8):1756–66.

    Article  CAS  PubMed  Google Scholar 

  80. Szeto C, Lobos CA, Nguyen AT, Gras S. TCR recognition of peptide-MHC-I: rule makers and breakers. Int J Mol Sci. 2020;22(1):E68.

    Article  Google Scholar 

  81. Schumacher TN, Scheper W, Kvistborg P. Cancer neoantigens. Annu Rev Immunol. 2019;26(37):173–200.

    Article  Google Scholar 

  82. Rock KL, Reits E, Neefjes J. Present Yourself! By MHC class I and MHC class II molecules. Trends Immunol. 2016;37(11):724–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Colbert JD, Cruz FM, Rock KL. Cross-presentation of exogenous antigens on MHC I molecules. Curr Opin Immunol. 2020;64:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71(7):1065–8.

    Article  CAS  PubMed  Google Scholar 

  85. Gameiro SF, Ghasemi F, Barrett JW, Nichols AC, Mymryk JS. High level expression of MHC-II in HPV+ head and neck cancers suggests that tumor epithelial cells serve an important role as accessory antigen presenting cells. Cancers (Basel). 2019;11(8):E1129.

    Article  Google Scholar 

  86. Homet Moreno B, Zaretsky JM, Garcia-Diaz A, Tsoi J, Parisi G, Robert L, et al. Response to programmed cell death-1 blockade in a murine melanoma syngeneic model requires costimulation, CD4, and CD8 T Cells. Cancer Immunol Res. 2016;4(10):845–57.

    Article  CAS  PubMed  Google Scholar 

  87. Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol. 2016;16(2):102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Abolhalaj M, Askmyr D, Sakellariou CA, Lundberg K, Greiff L, Lindstedt M. Profiling dendritic cell subsets in head and neck squamous cell tonsillar cancer and benign tonsils. Sci Rep. 2018;8(1):8030.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Le Gall CM, Weiden J, Eggermont LJ, Figdor CG. Dendritic cells in cancer immunotherapy. Nat Mater. 2018;17(6):474–5.

    Article  PubMed  Google Scholar 

  90. Wang Y, Xiang Y, Xin VW, Wang XW, Peng XC, Liu XQ, et al. Dendritic cell biology and its role in tumor immunotherapy. J Hematol Oncol. 2020;13(1):107.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Gardner A, de Mingo PÁ, Ruffell B. Dendritic cells and their role in immunotherapy. Front Immunol. 2020;11:924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24.

    Article  CAS  PubMed  Google Scholar 

  93. Gerhard GM, Bill R, Messemaker M, Klein AM, Pittet MJ. Tumor-infiltrating dendritic cell states are conserved across solid human cancers. J Exp Med. 2021;218(1): e20200264.

    Article  CAS  PubMed  Google Scholar 

  94. Veglia F, Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol. 2017;45:43–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123(7):2873–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hoesli R, Birkeland AC, Rosko AJ, Issa M, Chow KL, Michmerhuizen NL, et al. Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma. Oral Oncol. 2018;77:83–9.

    Article  CAS  PubMed  Google Scholar 

  97. Corgnac S, Boutet M, Kfoury M, Naltet C, Mami-Chouaib F. The emerging role of CD8+ tissue resident memory T (T RM) cells in antitumor immunity: a unique functional contribution of the CD103 integrin. Front Immunol. 2018;9:1904.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Beumer-Chuwonpad A, Taggenbrock RLRE, Ngo TA, van Gisbergen KPJM. The potential of tissue-resident memory T cells for adoptive immunotherapy against cancer. Cells. 2021;10(9):2234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kumai T, Lee S, Cho HI, Sultan H, Kobayashi H, Harabuchi Y, et al. Optimization of peptide vaccines to induce robust antitumor CD4 T-cell responses. Cancer Immunol Res. 2017;5(1):72–83.

    Article  CAS  PubMed  Google Scholar 

  101. Melssen M, Slingluff CL. Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol. 2017;47:85–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Son YM, Cheon IS, Wu Y, Li C, Wang Z, Gao X, et al. Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses. Sci Immunol. 2021;6(55):eabb6852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Deng WW, Li YC, Ma SR, Mao L, Yu GT, Bu LL, et al. Specific blockade CD73 alters the “exhausted” phenotype of T cells in head and neck squamous cell carcinoma. Int J Cancer. 2018;143(6):1494–504.

    Article  CAS  PubMed  Google Scholar 

  104. Watermann C, Pasternack H, Idel C, Ribbat-Idel J, Brägelmann J, Kuppler P, et al. Recurrent HNSCC harbor an immunosuppressive tumor immune microenvironment suggesting successful tumor immune evasion. Clin Cancer Res. 2021;27(2):632–44.

    Article  CAS  PubMed  Google Scholar 

  105. Hayashi R, Nagato T, Kumai T, Ohara K, Ohara M, Ohkuri T, et al. Expression of placenta-specific 1 and its potential for eliciting anti-tumor helper T-cell responses in head and neck squamous cell carcinoma. Oncoimmunology. 2020;10(1):1856545.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, et al. Resistance to radiotherapy and PD-L1 blockade Is mediated by TIM-3 upregulation and regulatory T-cell infiltration. Clin Cancer Res. 2018;24(21):5368–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Moreira D, Sampath S, Won H, White SV, Su YL, Alcantara M, et al. Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity. J Clin Invest. 2021;131(2): 137001.

    Article  PubMed  Google Scholar 

  108. Birkeland AC, Rosko AJ, Beesley L, Bellile E, Chinn SB, Shuman AG, et al. Preoperative tracheostomy is associated with poor disease-free survival in recurrent laryngeal cancer. Otolaryngol Head Neck Surg. 2017;157(3):432–8.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Schuler PJ, Harasymczuk M, Visus C, Deleo A, Trivedi S, Lei Y, et al. Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res. 2014;20(9):2433–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Whiteside TL, Ferris RL, Szczepanski M, Tublin M, Kiss J, Johnson R, et al. Dendritic cell-based autologous tumor vaccines for head and neck squamous cell carcinoma. Head Neck. 2016;38(Suppl 1):E494-501.

    Article  PubMed  Google Scholar 

  111. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.

    Article  CAS  PubMed  Google Scholar 

  112. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cramer JD, Burtness B, Ferris RL. Immunotherapy for head and neck cancer: recent advances and future directions. Oral Oncol. 2019;99: 104460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Xie X, O’Neill W, Pan Q. Immunotherapy for head and neck cancer: The future of treatment? Expert Opin Biol Ther. 2017;17(6):701–8.

    Article  PubMed  Google Scholar 

  115. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gross S, Erdmann M, Haendle I, Voland S, Berger T, Schultz E, et al. Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients. JCI Insight. 2017;2(8):91438.

    Article  PubMed  Google Scholar 

  117. Whiteside TL. Head and neck carcinoma immunotherapy: facts and hopes. Clin Cancer Res. 2018;24(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  118. Miyauchi S, Kim SS, Pang J, Gold KA, Gutkind JS, Califano JA, et al. Immune modulation of head and neck squamous cell carcinoma and the tumor microenvironment by conventional therapeutics. Clin Cancer Res. 2019;25(14):4211–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gildener-Leapman N, Ferris RL, Bauman JE. Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral Oncol. 2013;49(12):1089–96.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Cramer JD, Burtness B, Le QT, Ferris RL. The changing therapeutic landscape of head and neck cancer. Nat Rev Clin Oncol. 2019;16(11):669–83.

    Article  PubMed  Google Scholar 

  121. García-Foncillas J, Sunakawa Y, Aderka D, Wainberg Z, Ronga P, Witzler P, et al. Distinguishing features of cetuximab and panitumumab in colorectal cancer and other solid tumors. Front Oncol. 2019;9:849.

    Article  PubMed  PubMed Central  Google Scholar 

  122. FDA Approves ERBITUX® (cetuximab) for First-Line Recurrent Locoregional or Metastatic Head and Neck Cancer in Combination with Platinum-based Chemotherapy with 5-Fluorouracil | Eli Lilly and Company [Internet]. [cited 2022 Jul 10]. https://investor.lilly.com/news-releases/news-release-details/fda-approves-erbituxr-cetuximab-first-line-recurrent

  123. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.

    Article  CAS  PubMed  Google Scholar 

  124. Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40–50.

    Article  CAS  PubMed  Google Scholar 

  125. Gebre-Medhin M, Brun E, Engström P, Haugen Cange H, Hammarstedt-Nordenvall L, Reizenstein J, et al. ARTSCAN III: a randomized phase iii study comparing chemoradiotherapy with cisplatin versus Cetuximab in patients with locoregionally advanced head and neck squamous cell cancer. J Clin Oncol. 2021;39(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  126. Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Fornasier G, Francescon S, Baldo P. An update of efficacy and safety of Cetuximab in metastatic colorectal cancer: a narrative review. Adv Ther. 2018;35(10):1497–509.

    Article  PubMed  Google Scholar 

  128. Cabezas-Camarero S, Cabrera-Martín MN, Merino-Menéndez S, Paz-Cabezas M, García-Barberán V, Sáiz-Pardo Sanz M, et al. Safety and efficacy of Cetuximab-based salvage chemotherapy after checkpoint inhibitors in head and neck cancer. Oncologist. 2021;26(6):e1018–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mei M, Chen YH, Meng T, Qu LH, Zhang ZY, Zhang X. Comparative efficacy and safety of radiotherapy/cetuximab versus radiotherapy/chemotherapy for locally advanced head and neck squamous cell carcinoma patients: a systematic review of published, primarily non-randomized, data. Ther Adv Med Oncol. 2020;12:1758835920975355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chandler NJ, Call MJ, Call ME. T cell activation machinery: form and function in natural and engineered immune receptors. Int J Mol Sci. 2020;21(19):E7424.

    Article  Google Scholar 

  131. Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell. 2019;36(5):471–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kosti P, Maher J, Arnold JN. Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front Immunol. 2018;9:1104.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Gowrishankar K, Birtwistle L, Micklethwaite K. Manipulating the tumor microenvironment by adoptive cell transfer of CAR T-cells. Mamm Genome. 2018;29(11–12):739–56.

    Article  CAS  PubMed  Google Scholar 

  134. Larcombe-Young D, Papa S, Maher J. PanErbB-targeted CAR T-cell immunotherapy of head and neck cancer. Expert Opin Biol Ther. 2020;20(9):965–70.

    Article  PubMed  Google Scholar 

  135. van Schalkwyk MCI, Papa SE, Jeannon JP, Guerrero Urbano T, Spicer JF, Maher J. Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer. Hum Gene Ther Clin Dev. 2013;24(3):134–42.

    Article  PubMed  Google Scholar 

  136. Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):3293–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  138. Outh-Gauer S, Alt M, Le Tourneau C, Augustin J, Broudin C, Gasne C, et al. Immunotherapy in head and neck cancers: a new challenge for immunologists, pathologists and clinicians. Cancer Treat Rev. 2018;65:54–64.

    Article  CAS  PubMed  Google Scholar 

  139. Outh-Gauer S, Morini A, Tartour E, Lépine C, Jung AC, Badoual C. The microenvironment of head and neck cancers: papillomavirus involvement and potential impact of immunomodulatory treatments. Head Neck Pathol. 2020;14(2):330–40.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Chen J, Yang J, Li H, Yang Z, Zhang X, Li X, et al. Single-cell transcriptomics reveal the intratumoral landscape of infiltrated T-cell subpopulations in oral squamous cell carcinoma. Mol Oncol. 2021;15(4):866–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mehra R, Seiwert TY, Gupta S, Weiss J, Gluck I, Eder JP, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer. 2018;119(2):153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kaidar-Person O, Gil Z, Billan S. Precision medicine in head and neck cancer. Drug Resist Updat. 2018;40:13–6.

    Article  PubMed  Google Scholar 

  143. Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21(6):360–78.

    Article  CAS  PubMed  Google Scholar 

  144. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, et al. Head and neck cancers, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(7):873–98.

    Article  PubMed  Google Scholar 

  145. Tahara M, Kiyota N, Yokota T, Hasegawa Y, Muro K, Takahashi S, et al. Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02). Ann Oncol. 2018;29(4):1004–9.

    Article  CAS  PubMed  Google Scholar 

  146. Yokota T, Homma A, Kiyota N, Tahara M, Hanai N, Asakage T, et al. Immunotherapy for squamous cell carcinoma of the head and neck. Jpn J Clin Oncol. 2020;50(10):1089–96.

    Article  PubMed  Google Scholar 

  147. Solomon B, Young RJ, Rischin D. Head and neck squamous cell carcinoma: genomics and emerging biomarkers for immunomodulatory cancer treatments. Semin Cancer Biol. 2018;52(Pt 2):228–40.

    Article  CAS  PubMed  Google Scholar 

  148. Yang X, Zhang X, Mortenson ED, Radkevich-Brown O, Wang Y, Fu YX. Cetuximab-mediated tumor regression depends on innate and adaptive immune responses. Mol Ther. 2013;21(1):91–100.

    Article  CAS  PubMed  Google Scholar 

  149. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915–28.

    Article  CAS  PubMed  Google Scholar 

  150. Sacco AG, Chen R, Worden FP, Wong DJL, Adkins D, Swiecicki P, et al. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol. 2021;22(6):883–92.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of Zhejiang Provincial (Grant Nos. LY19H160014, LY20H130001, LQ21H130001), Medical and Health Research Project of Zhejiang Province (Grant Nos. 2019ZD018, 2021KY307), Ningbo Health Branding Subject Fund (Grant No. PPXK2018-02), Ningbo Natural Science Foundation (Grant No. 202003N4239), the Ningbo “Technology Innovation 2025” Major Special Project (Grant Nos. 2018B10015, 2020Z097), and the Key Project of Teaching and Research of Ningbo University (Grant No. JYXMXZD2021033), and the 2022 postgraduate course construction project of Medical School of Ningbo University.

Funding

This work was supported by grants from the Natural Science Foundation of Zhejiang Province (Grant Nos. LY19H160014, LY20H130001, LQ21H130001), Medical and Health Research Project of Zhejiang Province (Grant Nos. 2019ZD018, 2021KY307), Ningbo Health Branding Subject Fund (Grant No. PPXK2018-02), Ningbo Natural Science Foundation (Grant No. 202003N4239), the Ningbo “Technology Innovation 2025” Major Special Project (Grant Nos. 2018B10015, 2020Z097), the Key Project of Teaching and Research of Ningbo University (Grant No. JYXMXZD2021033), and the 2022 postgraduate course construction project of Medical School of Ningbo University.

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  1. Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China

    Yizhen Xiang, Mengdan Gong, Yongqin Deng & Dong Ye

  2. Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated People Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China

    Hongli Wang

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XYZ wrote the major part of the manuscript. DYQ, GMD and WHL revised the manuscript. YD revised and reviewed the manuscript. All authors read and approved the final manuscript.

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Xiang, Y., Gong, M., Deng, Y. et al. T cell effects and mechanisms in immunotherapy of head and neck tumors. Cell Commun Signal 21, 49 (2023). https://doi.org/10.1186/s12964-023-01070-y

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Keywords

Cell Communication and Signaling

ISSN: 1478-811X