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| 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] |
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