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Fig. 3 | Cell Communication and Signaling

Fig. 3

From: The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

Fig. 3

Proposed mechanism of HMA-induced IFN response. The figure shows an epithelial tumor cell where the ERV promoters are methylated. Therapy with AZA/DAC leads to demethylation of ERV promoters (1), resulting in transcription of ERV genes, ssRNA and dsRNA (2). In the cytoplasm, ERV dsRNA is sensed by the pathogen recognition receptor (PRR) RIG1 and MDA5, which activate the transcription factors NFκB and IRF3 after binding to the adapter protein MAVS (3). The endosomal membrane-bound TLR-7 and -8 recognize endosomal ssRNA, and activate the transcription factors NFκB and IRF3 after binding to the adapter molecule MyD88 (4). The endosomal membrane-bound TLR-3 recognizes endosomal dsRNA, and activates the transcription factors IRF-5 and -7 after binding to the adapter molecule TRIF (5). These three pathways all drive the expression and secretion of interferon type 1 and 3 (INFI/III) (6). IFNI and III signal back via an autocrine feedback loop and the INF-receptor (IFNR), which signals via JAK/STAT (7). This results in the up-regulation and secretion of the chemokines CXCL9 and 10, which attract tumor-specific CTLs (8). In addition, AIM and ISGs are upregulated, which also aid in reactivation of dormant anti-tumor immunity (9). Furthermore, TAAs are upregulated (10), as are MHC-I molecules (11), which together enhance the immunologic visibility of the tumor cells and enable them to be recognized by the TCR of tumor-specific CTLs. Treatment with HMAs also results in the unwanted up-regulation of inhibitory immune checkpoint receptors (PD-1, CTLA-4) (12) and their ligands (PD-L1, PD-L2, CD80, CD86) (13), which can result in secondary resistance to HMAs, but may also be exploited as a sensitizing or priming strategy for targeted treatment with immune checkpoint modulators

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