Table 2.
Impact of secreted factors in the tumor microenvironment (TME) over the different immune cell populations and description of receptors acting as eat me or don’t eat me signals for phagocytic activity of macrophages.
| Factor | Type of cell | Effect | Reference |
|---|---|---|---|
| TGFβ | CD8 | Suppresses IFN-γ production | (33) |
| Th1 | Suppresses IFN-γ production and induces differentiation to T-reg and Th17 cells. | (34, 35) | |
| PB-NK | Converts cytotoxic CD56dim and CD56bright PB-NK cells into dNK-like cells. | (36, 37) | |
| Added to IL15 and IL18 the effects are enhanced. | (38) | ||
| PB-NK | Down-regulates NKP30, NKG2D and DAP10 and, consequently, NKG2D. | (39, 40) | |
| PB-NK | At low doses up-regulates CXCR4 and CXCR3. At high doses, down-regulates NKp30, limiting NK killer activity. | (41) | |
| PB-NK | In combination with hypoxia and 5-aza-2′-deoxycytidine polarizes PB-NK cells to dNK-like cells. | (37) | |
| IL10 | APCs | Down-regulates HLA-II on APCs inhibiting antigen presentation. | (42) |
| CD8 | Induces intratumoral antigen presentation with infiltration and activation of CD8 T cells expressing IFNγ and granzymes. | (43) | |
| HLA-G | CD8 | Up-regulates CTLA-4, PD-1, TIM-3, and CD95. | (44) |
| IFNγ | Tumor cells | PD-L1 up-regulation. | (45) |
| FGL1 | CD8 | LAG-3 up-regulation with T cell inhibition. | (46) |
| Gal-9 | Th1 | Loss of IFNg producing cells and suppression of Th1 autoimmunity. | (47) |
| Nectin-3 | T cells and monocytes | Promote lymphocyte transmigration through interaction with Nectin-2 on endothelial cells. | (48) |
| Nectin-2 | T cell | T cell homing migration to the spleen through TIGIT interaction. | (49) |
| PB-NK | Binds to TIGIT inhibiting NK cell cytotoxicity. | (50) | |
| PVR | PB-NK | Binds to TIGIT inhibiting NK cell cytotoxicity. | (50) |
| PGE2 | CD8 | Suppression of activity. | (51) |
| CD4 | Suppression of Th1 activity and promotion of Th2, Th17 and T-reg. | (51) | |
| PB-NK | In thyroid cancer and melanoma inhibits NKG2D, NKp44, NKp30, and TRAIL suppressing NK cell cytotoxicity. | (10, 52) | |
| PB-NK | In melanoma down-regulates NKp44 and NKp30 leading to NK cell inhibition. | (53) | |
| Macrophages | Reduction of CCL5 production. | (54) | |
| IDO | CART-19 | Inhibition of CART cell activity. | (55) |
| Lactic acid | CD8 | Suppresses nutrient uptake leading to impaired activation. | (56) |
| NK | Suppresses nutrient uptake leading to impaired activation. | (56) | |
| Glycodelin-A | CD56 bright PB-NK | Polarizes CD56bright into dNK-like cells. | (57) |
| HLA-G | PB-NK | Induction of senescence with SASP secretion promoting vascular remodeling and angiogenesis. | (58) |
| Hypoxia | T cells | Favors a glycolytic metabolism and increased lactate production, dampening T effector functions. | (59) |
| PB-NK | Avoids the ability to upregulate NKp46, NKp30, NKp44, and NKG2D in response to activating cytokines. | (60) | |
| PB-NK | Degrades NK cell granzyme B by autophagy. | (61) | |
| PB-NK | Reduced ability to release IFNγ, TNFα, GM-CSF, CCL3, and CCL5, and preservation of immature CD56bright NK cells expressing CCR7 and CXCR4, resembling dNK-like cells. | (62) | |
| Macrophages | Activates granulin expression in macrophages through VEGF, conferring increased angiogenic potential. | (63) | |
| Macrophages | In pancreatic cancer promotes release of exosomes containing miR-301a-3p that induce M2 polarization. | (64) | |
| Macrophages | Induces CXCL12 and CXCR4 expression, which modulate the migration of monocyte-derived macrophages, and TAMs. | (65) | |
| IL6 | Macrophage | Induces M2 polarization in colorectal cancer models. | (66) |
| OSM | Macrophage | M2 polarization via mTOR signaling complex 2-Akt1. | (67) |
| CCL2 | Macrophage | Recruitment of M1 to polarize them to metastasis-associated macrophages. | (68) |
| IL34 | Macrophage | Increase recruitment of M2 macrophages in osteosarcoma. | (69) |
| VEGF-A | Macrophage | With IL10 and IL4 secreted by tumor cells and macrophages, respectively, induced M2 polarization. | (70) |
| Versican | Macrophage | Activates macrophages to release TNFα enhancing growth of tumor cells. | (71) |
| MIF | Macrophage | Recruitment of macrophages through TGFβ secretion by Kupffer cells that creates a fibrotic microenvironment. | (72) |
| ST2 | Macrophage | M1 macrophage polarization in models of lung cancer. | (73) |
| miR-21 | Macrophage | Polarization of monocytes to M2 macrophages, secretion of IL6, IL8, CCL2, and CCL5. | (74) |
| CD47 | Macrophage | In tumor cells is a don’t eat me signal for macrophages. | (75) |
| PD-1 | Macrophage | Don’t eat signal in macrophages. | (76) |
| β2M subunit (HLA-I) | Macrophage | In tumor cells is a don’t eat me signal for macrophages through interaction with LILRB1. | (77) |
| CD24 | Macrophage | In tumor cells is a don’t eat me signal for macrophages. | (78) |
PB-NK, peripheral blood NK cells; dNK, decidual NK cells; T-reg, regulatory T cell; APCs, antigen presenting cells; IFN-γ, interferon-γ; TGFβ, transforming growth factorβ; FGL1, fibrinogen-like 1; GAL-9, galectin-9; IL, interleukin; HLA, human leukocyte antigen; miR, microRNA; OSM, oncostatin-M; VEGF, vascular endothelial growth factor; MIF, macrophages migration inhibitory factor; ST2, suppression of tumorigenicity 2.