Table 1.

Clinical significance and results of preclinical studies of ICs and their ligands.

Receptor	Results of Preclinical Stydies	Ligands	Clinical Significance/ Results of Preclinical Stydies
TIM-3	The use of mAbs against TIM-3 stimulates the production of IFNγ. The antitumor efficacy of anti-TIM-3 is associated with the ratio of CD8+:CD4+ T-cells in the TILs pool. The combined use of mAbs targeting TIM-3, PD-1, and CTLA-4 has been shown to be more effective and well tolerated [47]. In models of lung adenocarcinoma, it was found that the use of mAbs targeting PD-1 can increase the expression of TIM-3. The effectiveness of the use of TIM-3 in overcoming resistance to therapy with mAbs targeting PD-1 has been shown [48]. The expression of LAG-3 and CTLA-4 was increased on CD8+ T-lymphocytes bound by the used mAbs targeting TIM-3 and PD-1. The combined use of mAbs targeting TIM-3 and CTLA-4 shows a synergistic effect in models [49].	Phosphotidylserine	-
		Galectin-9	Resistance to anti-PD-1 therapy has been observed in the presence of TIM-3+ lymphocytes and galectin-9-expressing MDSC [17]. The co-expression of galectin-9 and TIM-3 has been detected in various types of cancer [14,19]. The correlation of galectin-9 expression with better OS (in HCC and CRC) or PFS (in GC and NSCLC) has been shown [20]. The opposite data are available [16].
		Alarmin-1 (HMGB1)	HMGB1 is associated with progression and metastasis in NSCLC and CRC [25,26].
		CEACAM1	A synergistic antitumor effect has been shown with the simultaneous blockade of TIM-3 and CEACAM1, as well as CEACAM1 and PD-L1, on CRC models [36]. In the early stages of CRC, CEACAM1 inhibits tumor cell proliferation [34]. However, CEACAM1 is a diagnostic and prognostic marker in melanoma, and CEACAM1 is found in tumor samples and sera from patients with PC and is overexpressed in advanced stages of CRC, NSCLC, and other cancers [39].
LAG-3	It has been shown that the therapeutic use of PD-1 leads to an increase in the expression level of LAG-3 [80]. In NSCLC, the co-expression of LAG-3 and PD-1 on TILs and PD-L1 on tumor cells is shown [81]. A synergistic effect was observed from the combined use of mAbs binds LAG-3 and PD-1 in various tumor models [82].	MHC class II	MHCII is associated with survival, increased numbers of CD4+ and CD8+ T -cells in the TILs, and a good response to anti-PD-1 and PD-L1 immunotherapy in some cancers [65].
		FGL-1	The FGL-1/LAG-3 interaction blockade stimulates tumor immunity [67]. The reduced expression of FGL-1 increases the efficiency of CD8+ T-cell activation during LAG-3 blockade [69].
		Galectin-3	The restoration of cytolytic functions of CD8+ T- cells in response to the inhibition of galectin-3 was shown, which indicates the role of galectin-3 in the suppression of antitumor immunity. The direct involvement of galectin-3 in the processes of metastasis was revealed [72,73,74], as well as the association of galectin-3 expression with poor clinical prognosis [75]. However, in melanoma and glioblastoma, the presence of galectin-3 is beneficial for patients [76].
		LSECtin	A high level of soluble LSECtin in the blood serum of patients with CRC is associated with the presence of liver metastases [78]. The expression of LSECtin and its interaction with LAG-3 molecules are shown on B16 melanoma cells. It is accompanied by the suppression of the T-cell antitumor response, and the blockade of LSECtin/LAG-3 interaction restores the secretion of IFNγ [79].
TIGIT	The blockade of TIGIT has been shown to prevent the depletion of NK cells and stimulate NK-mediated tumor immunity, activate antitumor T-cell immunity, and promote the formation of immune memory [122,129]. The co-inhibition of TIGIT and PD-1 or PD-L1 with mAbs exhibited a significant therapeutic effect, up to the complete elimination of tumors [122,124,125,126]. Using mAb against TIGIT showed: restoration of the functions of effector T-cells; the induction of cellular cytotoxicity against regulatory T-cells; a direct cytotoxic effect on TIGIT+ tumor cells [127,130]. The high efficiency of the combined inhibition of PD-1 and CD96 or TIGIT and CD96 has been shown [128].	Nectin-2 (CD112)	Interaction with TIGIT leads to the corresponding transmission of inhibitory signals to immune cells. Nectin-2 is expressed in breast and ovarian tumors [111].
		Nectin-4 (PVRL4)	Nectin-4 blocking Abs stimulates an NK-mediated antitumor response [113]. The participation of nectin-4 in the processes of proliferation, invasion, and metastasis through the activation of Pi3k/Akt and WNT/β-catenin signaling pathways has been shown [114]. The revealed hyperexpression of nectin-4 by tumor tissues is associated with tumor aggressiveness and poor clinical prognosis [115,116].
		PVR (CD155)	Overexpression and the presence of a soluble form of CD155 in the blood serum of patients are associated with a poor clinical prognosis [102,106,107]. The association of the co-expression of TIGIT and CD155 with an unfavorable disease course in lung adenocarcinoma and primary SCC of the esophagus has been shown [106,108].
VISTA	In response to blocking VISTA with the use of mAbs, an increase in the number of TILs and the restoration of the functions of CD8+ T-cells were observed [147]. An increase in the expression of chemokines (CXCL9/10, CCL4/5) as well as cytokines (IFNβ, IL6, IL12, IL23, IL27, TNFα) was observed in tumor tissues [146]. However, the effective suppression of tumor growth was observed only when anti-VISTA mAbs was used in combination with anti-PD-1 mAbs [171,173] or CTLA-4 [170]. The blockade of VISTA caused an increase in tumor infiltration by immune cells and a decrease in the number of myeloid suppressor cells (MSCs). The therapeutic effect of anti-VISTA antibodies has been demonstrated in OC models highly expressing VISTA [143].	VSIG-3 (IGSF11)	The expression of VSIG-3 by tumor tissues was found in CRC, HCC, and in intestinal-type GC [151]. The overexpression of VSIG-3 is associated with the expression of VISTA, as well as with PD-L1 and PD-1, with a high degree of tumor malignancy, and a poor clinical prognosis in glioblastoma has been revealed [152]. Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [174].
		PSGL-1	The ability of PSGL-1 to bind to VISTA was shown at acidic values of the medium (pH 6.0). At lower pH values, an enhanced inhibitory effect of VISTA was shown, and the use of Abs capable of blocking the VISTA/PSGL-1 interaction restored the proliferative and secretory functions of T-cells [153]. Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [174].
		Galectin-9	The study of samples from patients with peritoneal carcinomatosis showed a high level of expression of galectin-9, VISTA and TIM-3 depleted TILs [156].
BTLA	The antitumor efficacy of anti-BTLA mAbs has been shown [212,213]. In the blockade of BTLA, an increase in the proliferation and expansion of NY-ESO-1-specific CD8+ T-cells was observed, and an increased efficiency of the use of mAbs targeting BTLA in combination with anti-PD-1 and anti-Tim-3 in melanoma was shown [214]. An increase in median OS [215], as well as the enhancing T-cell proliferation and cytokine production, was observed with the combination of anti-BTLA and anti-PD-1 therapies [216].	HVEM (TNFRSF14)	T-cell activation is observed as a result of HVEM suppression in OC cells and in the ESCC cell line [195,196]. HVEM expression is associated with a decrease in the number of TILs and with a poor prognosis in ESCC and CRC, including in patients with CRC metastases to the liver and other oncological diseases [196,198,199,200,201]. The high expression of HVEM is associated with an increased risk of transformation, while transformed FL is characterized by a low level of BTLA expression and a high level of HVEM [202]. In GC, an overexpression of BTLA and HVEM is associated with a poor clinical prognosis [203].