Table 1.

Mechanisms involved in tumor escape in Cutaneous Melanoma. Examples of changes in tumor and immune cells derived from experimental models (syngeneic and xenograft murine models, as well as in vitro human models); and from clinical data from patients are described.

	Mechanism	Description	Examples
			Experimental models	Clinical data
	Evasion of Ag recognition by the IS	Loss of Ag expression; HLA-I loss; Ag plasticity; fails in Ag presentation	MART-1 loss after specific CTL treatment in xenografts [102]; TYR and TRP-2 loss in CM B16 [103]; HLA-I loss in xenografts [104, 105]; plasticity in MD-Ag and CD271 expression [101]	Tumor immunoediting in subsequent metastases [106]; MART-1 loss [107]; TAP-1 and MART-1 loss [71] β-2 microglobulin loss [108]; HLA-I, MART-1, and TYR loss [109]; gp100, TRP-2, SOX10, NY-ESO-1, and HLA-I loss [110]; MART-1/HLA-I loss after specific ACT [86]; plasticity in several Ag, including ABCB5 and CD271 [95]; plasticity in MD-Ag and CD271 expression [101]
Changes in tumor cells	Secretion of immunosuppressor factors	Factors interfering with NK, macrophages, DC, CD4 and CD8, function	HLA-G secretion in exosomes [111], NKG2DL downregulation [112], and HLA-E expression [113] impair NK/CD8 cytotoxicity. CCL21 expression induces lymphoid-like stroma, and recruits/activates Treg and MDSC in syngeneic and xenografts models [40]	IDO expression recruits Treg enabling mts [114, 115]; ICOS-L promotes activation and expansion of Treg [116]; IL-10 expression recruits Treg & TAM and is associated with CM progression [117]; TGF-β1 expression recruits tDC & Treg [39]; IDO, TGF-β, and CCL17/CCL22 expression in genome-wide association studies [118];
	Secretion of proapoptotic factors	Factors inducing apoptosis in effector T cells (tumor counterattack)	FasL expression [119], PD1L (B7-H1) expression [120], and FASL and TRAIL expression induces T-cell apoptosis [121, 122]	Gal-3 expression induces apoptosis in TIL [51]; Gal-3 is a marker of progression [123]; Gal-1 & Gal-3 expression in genome-wide association studies [118]
Changes in IS cells	Natural killer cells (NK cells)	Impaired effector function	Gal-3 impairs NK cytotoxicity in CM B16 [52]	Impaired lytic granule polarization by HLA-G [113, 124]; loss of activating Rc CD161 & NKG2DR expression in CM mts [125]; loss of activating Rc (NKG2DR), increase of inhibitory Rc (CD158b), and impaired activity (lower CD107a, IFN-γ and TNF-α expression) in CM mts [47, 48]
	Cytotoxic T cells (CTL)/CD8 cells	Impaired effector function	TCR zeta-chain downregulation [126]	Decreased expression of IL-2, IL-4 and IFN-γ by TIL [127]; tolerance induction in mts, with loss of IFN-γ and perforin expression [49]; low proportion of CD8+CD27− cytolytic cells in primary CM [50]
	Regulatory T cells (Treg)	They secrete immunosuppressive factors interfering with NK, macrophages, DC, CD4, and CD8 function	Treg inhibit FasL-induced innate and adaptive tumor immunity in CM B16 [128]	Induce immunotolerance in CM genesis [41]; upregulated in LN+ [129] and advanced CM [130]; Treg impairs NY-ESO-1 vaccine [131, 132]; secrete IL-10 [39]; Treg IDO+ as a negative survival prognostic marker for SLN− patients [42]
	Tolerogenic dendritic cells (tDC)	tDCs have diminished Ag presentation and T-cell activation; induce anergy and tolerance in T-cells	P38 MAPK expression drives tDC in CM progression [133]	Upregulation in advanced patients [130]; TGF-RβI promotes tDC, expressing IDO and TGF-β2 [39]
Changes in IS cells	Plasmacytoid dendritic cells (pDC)	Induce strong immunosuppression	IDO expression and strong immunosuppression in mouse tumor-draining LN [134]	Related to poor prognosis in primary CM [44]; CCR6/CCL20 interaction involved in pDC recruitment to the tumor [135]; pDC associates with SLN+ [45] and express IDO [46]
	Tumor-associated macrophages (TAM)	M2-polarized TAM release immunosuppressor, proangiogenic, and growth factors	MCP-1 recruits TAM [57]; Adrenomedullin expression by TAM [58] is related to CM angiogenesis and growth.	Cyclooxygenase-2 expression in TAM as a marker of CM progression [59]; TAM impairs NY-ESO-1 vaccine [131]
	Myeloid-derived suppressor cells (MDSC)	Progenitor and immature myeloid cells induce Treg; aminoacids depletion; TCR modification	Treg recruits MDSC and induces B7-H1 and IL-10 expression in CM [60]; chronic inflammation recruits MDSC to tumor and impairs T-cell function [61]; MDSC enables CM mts [62]	Upregulated in advanced CM, MDSC immunosuppress CD4 and CD8 function [63]
	Tumor-associated neutrophils (TAN)	Promote chronic inflammation and tumor migration	Mac-1 (TAN)/ICAM-1 interaction promotes CM cells migration [64]	TAN associated with poor prognosis in primary CM [44], and an independent negative OS factor in advanced CM patients [65]
	Mast cells	Promote chronic inflammatory environment and angiogenesis	Il-8 inflammatory cytokine secretion by CM cells induced by mast cells [66]	Mast cells (tryptase+) association with VEGF expression and angiogenesis in CM [67]; mast cells correlation with poor CM prognosis [68]