Table 1.
Positive signals of T-cell infiltration.
| Signal/Receptor | Producer/Target | Mechanisms | Therapy |
|---|---|---|---|
| IFNG/IFNGR1+IFNGR2 | Cytotoxic T cells/endothelial cell, fibroblasts, tumor cell, monocyte | Interferon-γ induces CXCR3 ligands (CXCL9,10,11), thus enhancing the CXCR3-mediated T-cell recruitment (15). | Intravesical instillation of recombinant interferon-γ inhibits the recurrence of bladder tumors in patients (16). |
| (fn. 1) IL6/IL6R+IL6ST | T cell, macrophage, endothelial cell, epithelial cell/endothelial cell | IL6 trans-signaling enhances both E- and P-selectin interactions and ICAM1 dependent T-cell transmigration on tumor vessels (17). | IL6-rich tumor microenvironment provided by systemic thermal therapy improves cytotoxic T cells’ delivery to tumor lesions in mouse tumors and patient tumor explants (13). |
| IL12A+IL12B/IL12RB1 + IL12RB2 | Phagocytic macrophage, DC/MDSC | IL12 may attenuate the impaired T-cell trafficking mediated by MDSCs by decreasing the percentage of MDSCs in tumors (18). | Treatment of IL12 significantly altered the phenotype and suppressive function of MDSC in mice (18). |
| (fn. 2) TNF/ITGAV | Lymphoid, mast, endothelial, fibroblast, tumor cell/ endothelial cell (19). |
TNF stimulation induces ICAM1 and VCAM1 expression on endothelial cells for T-cell extravasation (14). | The systemic administration of TNF had severe toxicity (20). The fusion of TNF and ITGAV ligand had antitumor effects in mice (21) |
| CXCL9,10,11/CXCR3 | Endothelial, fibroblast, tumor cell, monocyte/CXCR3+ T cell | These chemokines are induced by interferon-γ and share a receptor CXCR3, directing the migration of activated T and NK cells (22). | Virus-directed expression of CXCL10, 11, or recombinant CXCL10 injection in tumors can recruit anticancer T cells in mice (23–26). |
| CXCL16/CXCR6 | Tumor cell, macrophage, DC, Fibroblast/activated T cell, Th1, NK cell | CXCL16 is chemotactic for cells expressing its receptor CXCR6 (27, 28). | |
| CCL2/CCR2 | Endothelial cells/Th1, CD8 T | Actin fibers beneath the endothelial plasma membranes will dock vesicles storing CCL2. The tight lymphocyte-endothelial synapses will release the chemokine to promote the transendothelial T-cell migration (29). | CAR/CCR2 T cells displayed greater homing and tumor-killing in malignant pleural mesothelioma (30) and neuroblastoma tumors (31) in mice. |
| CCL3, 4, 5 (fn. 3)/CCR5 | Epithelial cell, fibroblast, monocyte, NK cell, DC, endothelial cell, macrophage, lymphocyte/CCR5+ DC | CCL3,4,5 can indirectly promote effector T-cell recruitment by recruiting the DCs into tumor sites. Then, DC, in turn, recruits cytotoxic T cells into the tumor by producing CXCR3 ligands CXCL9 and CXCL10 (32, 33). | Combining adenoviral delivery of CCL3 with the adoptive transfer of activated effector T cells significantly attracted activated T cells to the murine melanoma tumors (34). |
| CCL21/CCR7 | Lymphatic vessels, fibroblasts, HEV in lymph nodes/CCR7+ T cell, DC (35, 36) | CCL21 can significantly increase the CD4+ and CD8+ T cells, and DCs infiltration to tumors (37, 38). | Intratumoral injection of CCL21 induced DC and T-cell infiltration, causing tumor reduction in a murine lung cancer model (39). |
| CCL27/CCR10 | Keratinocytes/CCR10+ skin-homing T cells | Skin-associated chemokine CCL27 is specifically expressed in epidermal keratinocytes and mediates the recruitment of skin-homing CCR10+ memory T cells to cutaneous sites (40). | The tumor injection of adenoviral vector encoding CCL27 attracted T cells and suppressed tumor growth in a murine melanoma model (41). |