Table 2.
Negative signals of T-cell infiltration.
| Signal/Receptor | Producer/Target | Mechanisms | Therapy |
|---|---|---|---|
| IL35 (IL12A+IL27B)/(fn. 4) IL12RB2+IL6ST | Tregs, macrophages, B cell/T cell | Treg cells derived IL35 can decrease the intratumoral CD4+ and CD8+ T cells infiltration. Also, the infiltrated T cells displayed a less activated, effector memory phenotype (42). | Neutralization of IL35 enhances antitumor immunity in a genetically induced KP mouse model (42). |
| TGFB1/TGFBR1, 2, 3 | Fibroblasts/Tumor epithelial cell | TGFβ is a well-known regulator of EMT. Fibroblast induced TGFβ may reprogram peritumoral stromal fibroblasts and exhibit a fibroblast- and collagen-rich tumor (43), which will decrease the CD8+ T effector cell penetration in the tumor (44). | Inhibitors of TGFβ and receptors have entered clinical trials (45–48). CAR-T cells expressing a dominant-negative TGF-βRII enhance T-cell expansion and prostate cancer eradication in clinical trials (49). |
| CXCL1, 2, 5/CXCR2 | Tumor cell, macrophage, neutrophil/CXCR2+ MDSC | CXCL1, 2, 5- CXCR2 signal promotes the recruitment of MDSC to tumors (50). | Several CXCR2 antagonists and inhibitors have been tested in preclinical models and shown anticancer effects (51, 52). |
| (fn. 5) CXCL8/CXCR1, 2 | Tumor cells, mast cells, TAM, endothelial cells/CXCR1, 2+ Neutrophil, MDSC | CXCL8 (IL8) enhances the infiltration of immune-suppressive cells expressing receptors (CXCR1, 2), such as tumor-associated neutrophils and MDSCs (53). T cells do not express CXCR1 and CXCR2 (54). | CXCR1 or CXCR2 modified CARs markedly enhance T-cell homing and persistence in murine GBM tumors (54). |
| CXCL12/CXCR4 | FAP+ CAF/CXCR4+ MDSC, Endothelial cell, T cell | CXCL12 has chemo-repulsive effects on T cells (55). CXCL12 promotes angiogenesis by recruiting endothelial precursor cells (56). CXCL12 also recruits MDSCs to tumors (57). |
AMD3100, a CXCR4 inhibitor, induced rapid T-cell accumulation around cancer cells in mice (58). |
| CCL2/CCR2 | Endothelial cell, tumor cell, fibroblast, monocyte/CCR2+ TAM, MDSC, Treg | Soluble CCL2 promotes the recruitments of TAM, MDSC, and Treg to the tumor sites (59–61). | |
| CCL5/CCR5 | Epithelial cell, fibroblast, monocyte, NK cell, DC, endothelial cell, macrophage, lymphocyte/CCR5+ TAM, Treg | CCL5 regulates TAM and MDSC migration (62). It can also recruit Treg to tumors (63). | |
| CCL17/CCR4, 8 | DC, Endothelial cell/CCR4+, CCR8+ cells. | CCL17 induces chemotaxis in CCR4+ T cells, mainly Th2 and Tregs, generating an immunosuppressive TME (64, 65). | CAR- CD30 coexpressing CCR4 T cells have an improved homing and antitumor activity in the murine Hodgkin tumor model (66). |
| CCL22/CCR4 | TAMs/CCR4+ Treg, | CCL22 enhances the recruitment of Tregs, thus decreasing effector T-cell homing (67). | |
| CCL28/CCR10 | Tumor cells/CCR10+ skin-homing T cells | CCL28/CCR10 signals promote Treg recruitment in hypoxic tumors (68). | |
| VEGF/VEGFR1, 2, NRP1 | Tumor, Macrophage, Endothelial, Fibroblast/Endothelial cell, Treg, MDSC | VEGF induces FASLG on endothelial cells, leading to T-cell apoptosis during extravasation (69). VEGF recruits the NRP1+ Tregs and VEGFR1,2+ MDSCs (70, 71). | The anti-VEGF/VEGFR is a standard therapy for many tumor types (72). |
| FGF2/FGFR1,2,3,4 | CAF/Endothelial cells | FGF2 significantly blocks the adhesion molecules VCAM1 and E-selectin expression (73). | |
| PDGFC/PDGFRA | CAF/Endothelial cells | PDGFC acts as a proangiogenic signal (74). | |
| PGF/FLT1 | TAMs/Endothelial cells | TAM production of PGF stimulates angiogenesis (75). |