Table 3.

Positive signals of T-cell survival.

Signal/Receptor	Producer/Target	Mechanisms	Therapy
(fn. 6) IL2/IL2RA,B,G	DC, activated T cells/effector T cell, Treg	CD8+ T cells depend on IL2 for sustained expansion (114, 115). However, the high-affinity IL2RA is not only expressed on activated T cells but also on Tregs, which is the primary barrier for the clinical application of IL2 (116).	IL-2 was one of the first FDA-approved immunotherapies for metastatic melanoma and renal cell cancer (94, 117), (fn. 7). Since IL2 expands effector T cells at the cost of Treg proliferation, engineered IL2 is necessary to preferentially target IL2 receptors on effector T cells (107).
IL7/IL7R+IL2RG	Fibroblastic reticular cell/T cell	IL7 promotes the homeostasis and expansion of naive and memory T cells by up-regulating BCL2 (118, 119), and suppressing pro-apoptotic mediators (120).	Coexpressing the IL7R with CAR-GD2 T cells activates STAT5 signaling and shows super antitumor response in metastatic neuroblastoma and glioblastoma mice model (104). Clinical trials using recombinant IL7 as monotherapy showed increases in CD4 and CD8 T cells with a decrease in Tregs in multiple cancer types (95, 121).
(fn. 8) IL10/IL10RA+IL10RB	Treg, Th1, DC, macrophage, epithelial cell/Tumor-resident T-cell (122).	IL10 directly activates and expands tumor-resident T cells without de novo infiltration from secondary lymphoid organs (123).	Treatment with pegylated IL10 restores tumor-specific CD8 T-cell accumulation and controls tumor growth in mice (124).
IL12A, IL12B/IL12RB1 + IL12RB2	Phagocytic cells, B cells, DC/T cells	IL12 stimulates activated T-cell proliferation (125).	Intratumoral injection of a recombinant retrovirus vector expressing IL-12 induces antitumor and anti-angiogenic effects in murine models of head and neck squamous cell carcinoma (99) and melanoma (100). The phase I trial of (fn. 9) NHS-IL12 in metastatic or locally advanced solid epithelial or mesenchymal tumors showed enhanced antitumor activity with increasing immune cell infiltration (126).
(fn. 6) IL15/IL15RA, IL2RB, IL2RG	Monocytes, macrophages, DC/CD8+ T cell	The IL15-IL15RA signaling triggers the downstream JAK1, JAK3, STAT3, and STAT5, which stimulates T-cell proliferation and survival (127). IL15 inhibits AICD and maintains T cells’ homeostatic proliferation.	IL15 has entered the clinical trial in patients with metastatic melanoma, renal cell carcinoma, and non-small cell lung cancer in CAR-T therapy and combination treatment with anti-PD1 antibody (96, 97, 128).
IL18/IL18R1+IL18RAP	Activated macrophages and Kupffer cells/T cells,	Combined stimulation with IL12 and IL18 can stimulate memory T cells in an antigen non-specific manner (129, 130). IL12 and IL18 may synergize with each other to induce Th1 differentiation (131).
IL21/IL21RA, IL2RG	Th17, Tfh, NKT cells/T cell	IL21 synergistically works with IL15 to expand CD8+ memory T cells (98). IL21 also suppresses Foxp3-expressing cells (132).	The combined administration of IL21 and IL15 dramatically increased the CD8+ T cells and resulted in tumor regression in mice melanoma models (98). Likewise, the combination treatment of IL21 with IL7 promotes the expansion of CAR-T cells with a TSCM phenotype (133).
CD27L/CD27	T cells/T cells	The CD27L/CD27 signaling plays an essential role in T-cell differentiation, survival, and memory T-cell formation (19, 134).	CD27 agonist showed antitumor efficacy in mice models (135) and phase I and II clinical trials of advanced solid tumors (108, 136),
41BBL/41BB	DC, macrophages, B cells, T cells/activated T cell	41BBL facilitates cell activation, survival, and proliferation upon binding to 41BB on T cells (137).	41BBL armored CAR T-cells showed enhanced in-vitro and in-vivo efficacy (138).
CCL19/CCR7	Fibroblastic reticular cell/T cell	T zone fibroblastic reticular cells can prevent the death of naive and memory T cells by secreting CCL19 (139, 140).	CCL19 CAR-T achieved superior antitumor activity compared to conventional CAR-T in mice (103).
CCL21/CCR7, CXCR3	Lymphatic vessels, stroma cells, HEV in lymph nodes/CCR7+, CXCR3+ cells (35, 36)	CCL21 promotes the expansion of naive T cells in tumors (141).	Delivery of CCL21 to metastasis tumors enhances the ACT efficacy by promoting the T-cell survival and cytotoxic activity in mice (142).