Fig. 2

TAM - PtdSer interactions in the tumor microenvironment. Autocrine and paracrine cross-signaling through PtdSer-TAM in a tumor setting. (a) Both cancer cells and the different TME cellular compartments express TAM receptors and secrete PROS1 and GAS6. The abundance of PtdSer enables potent autocrine (1) and / or paracrine (2) activation of TAM receptors expressed by tumor cells, resulting in augmented aggressiveness, also by inducing expression of the immune evasion/checkpoint molecules PD-L1 on cancer cells (3, [66]). Tumor-derived TAM ligands suppresses macrophage and T cell infiltration (4, [69, 70]. Similarly, the antitumor cytotoxicity of NK cells is suppressed by TAM receptor expression (5, [33]. (b) PtdSer-TAM signaling plays a role in immune cells, where they dampen inflammation, as described for the interactions between T and dendritic cells (6, [23]). Within T cells, opposing roles for TAM signaling report MERTK-dependent signaling to suppresses T cell activation and promote immune evasion through induction of PD-1 expression (7, [71]), but also to provide co-stimulatory functions (8, [72]). (c) In the case of macrophages, reports indicate that PstSer-TAM signaling is chiefly anti-inflammatory due to autocrine signaling within M1 and M2-like macrophages (9, [73]), and shifts M1-like pro-inflammatory macrophages towards the anti-inflammatory M2-like state (10, [74]), but also promotes anti-immunity through PD-L1 and PD-L2 expression (11, [71]). Altogether, although PtdSer-TAM signaling may result in opposing outcomes, the net effect of all interactions contributes to the generation of tumors with superior tumorigenic characteristics, within a more permissive environment. See text for details. Abbreviations: CAFs – cancer associated fibroblasts; BV – blood vessel; Tc – T cells; NK – natural killer, MDSCs – myeloid derived suppressor cells; DCs – dendritic cells; MФ – macrophage; TME – tumor microenvironment