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Immune Checkpoint Receptors
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Anticancer therapy based on the inhibition of immune checkpoints (ICs) is an actively developing field of study, and it has been widely used. Antibodies blocking immune checkpoints are used as therapeutics. The targeted checkpoints are mainly the PD-L1 (programmed death-ligand 1), expressed by the tumor, and the PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) immune cell receptors. To increase the effectiveness of therapy by blocking ICs, additional receptors and ligands are being investigated as targets of immunotherapy.

immune checkpoint expression therapy
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Subjects: Oncology
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Revisions: 3 times (View History)
Update Date: 13 Sep 2022
Table of Contents

    1. TIM-3

    TIM-3 (T-cell immunoglobulin and mucin domain-3) is a transmembrane protein, expressed by T-cells, IFNγ-secreting T-regulatory cells (Treg), natural killer cells (NK cells), dendritic cells (DCs), macrophages, and mast cells [1]. TIM-3 is a receptor, an immune response regulator that ensures the formation of immunological tolerance and prevents the occurrence of autoimmune diseases by regulating the homeostasis of T-helper type 1 [2]. A decreased expression level of TIM-3 is associated with the development of diabetes and multiple sclerosis [3]. At the same time, the overexpression of Tim3 can contribute to the depletion of T-cells by limiting the pool of memory T-cells while enhancing the initial activation of T-cells and the generation of short-lived effector cells in acute and chronic infections [4]. In addition, the participation of TIM-3 in the activation of mast cells was revealed [5]. Increased TIM-3 expression by tumor-infiltrating lymphocytes (TILs) is indicated in many malignant neoplasms and is characteristic of effector lymphocytes with a depleted phenotype [6][7]. On the other hand, TIM-3 expression is characteristic of activated regulatory T-cells with immunosuppressive activity [8]. A significant role of TIM-3, expressed in antigen-presenting cell (APC) and T-cells, in the regulation of CD8+ TILs trogocytosis in tumors has been shown. The use of mAb to TIM-3 is able to counteract the fratricidal process undergone by trogocytosed CD8+ T-cells [9].

    2. LAG-3

    The LAG-3 (lymphocyte-activation gene 3) gene (CD223) encodes a protein that negatively regulates the activation, proliferation, effector functions, and homeostasis of T-cells [10][11] and dendritic cells participating in preventing the development of autoimmune reactions in normal tissues [12] and regulating the immune response in chronic infections [13]. Due to the partial similarity of extracellular domains, LAG-3 and CD4 were presumably developed by gene duplication. However, differences in their intracellular domains result in their opposite functions [14]. The LAG-3 protein is presented in a transmembrane and soluble form (sLAG-3) formed by alternative splicing. It has been shown that under the action of ADAM10 and ADAM17 metalloproteases, the extracellular part of the receptor also passes into a soluble form [15]. LAG-3 is constitutively expressed by natural T-regulatory cells (Tr1), DCs, NK cells, and B-cells and is not found on naive T-cells; however, its expression is strongly increased after the activation of CD4+ and CD8+ lymphocytes, including TILs [16]. The modulating functions of LAG-3 correlate with the level of receptor expression [17]. The activation of LAG-3 reduces the production of various immunostimulatory interleukins (IL) and increases sensitivity to Treg signaling, thereby increasing T-cell tolerance and accelerating their depletion [16].

    3. TIGIT

    TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains) is a co-inhibitory receptor, expressed by all types of T-lymphocytes, as well as NK cells [18]. The receptor is involved in maintaining self-tolerance. The positive effect of TIGIT in regenerative hyperplasia was revealed: the absence of the receptor impairs liver regeneration in vivo [19].
    Several immunoregulatory mechanisms involving TIGIT have been described to date. The interaction of TIGIT with the ligand causes the phosphorylation of its cytoplasmic domain, which triggers processes that block the transmission of intracellular signals along the PI3K and MAPK pathways and the activation of NF-κB, which, in turn, leads to the suppression of the cytotoxic functions of NK cells [20]. In addition, the interaction of this receptor with the ligand leads to the phosphorylation of the latter and the triggering of modulating signals in DCs [21]. TIGIT has been reported to directly inhibit T-cell proliferation and effector functions by downregulating T-cell receptor (TCR) and activating CD28 signaling [22].

    4. VISTA

    VISTA (V-domain Ig suppressor of T-cell activation) or PD-1H (programmed death-1 homolog) is predominantly expressed by myeloid cells, as well as by CD4+ and Foxp3+ T-regulatory cells [23]. Studies of VISTA expression in cancer diseases have shown the presence of protein on TILs and macrophages and its absence on cells of most types of tumors [24]. However, in a number of studies, the expression of VISTA by tumor cells was detected in different proportions of samples in non-small cell lung cancer (NSCLC), [25], hepatocellular carcinoma [26], ovarian and endometrial cancer [27], melanoma, stomach cancer, and breast cancer [28]. VISTA negatively regulates T-cell activation, proliferation, and cytokine production [29] and specifically suppresses the immune response mediated by CD4+ T-cells [30]. However, in a study by Mercier et al., the suppression of lymphocyte functions was mediated by the activation of cell receptors by a fusion protein (VISTA-Ig) acting as a ligand [31]. On the other hand, the increased proliferation and production of VISTA−/− cytokines by CD4+ T-cells indicates VISTA receptor function [30]. In addition, VISTA directly regulates the effector functions of myeloid cells [32]. Thus, understanding the complex functioning of VISTA requires a detailed study of the associated immune regulatory mechanisms.

    5. BTLA

    BTLA (B- and T-lymphocyte attenuator) or CD272 is a transmembrane receptor expressed by naive T-lymphocytes, B-cells, macrophages, DCs, and natural killer T-cells (NKT) [33][34]. BTLA is involved in the regulation of immune cell homeostasis by inhibiting proliferation, the activation of B- and T-cells, and the production of cytokines [35]. In particular, BTLA negatively regulates the expansion and function of γδ T-cells [36], various subtypes of which both contribute to the progression of cancer and have antitumor activity [37]. A soluble form of the BTLA protein (sBTLA) is described as a potential prognostic and predictive marker in patients with clear cell renal cell carcinoma, pancreatic adenocarcinoma, and prostate cancer [38][39][40].
    A recent study in patients treated with immune checkpoint (ICT) inhibitors for solid tumors found an association between serum levels of soluble BTLA (sBTLA) and median overall survival [41].
    Data on the clinical significance of the molecules considered in the table, as well as the results of preclinical studies, are presented in Table 1.
    Table 1. Clinical significance and results of preclinical studies of immune checkpoints (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 (programmed cell death protein 1), and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) has been shown to be more effective and well tolerated [42].
    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 [43]. 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 [44].
    Phosphotidylserine -
    Galectin-9 Resistance to anti-PD-1 therapy has been observed in the presence of TIM-3+ lymphocytes and galectin-9-expressing myeloid-derived suppressor cells (MDSC)  [45].
    The co-expression of galectin-9 and TIM-3 has been detected in various types of cancer [46][47]. The correlation of galectin-9 expression with better overall survival (OS) (in hepatocellular carcinoma (HCC) and colorectal cancer (CRC)) or progression-free survival (PFS) (in gastric cancer (GC) and NSCLC) has been shown [48]. The opposite data are available [49].
    Alarmin-1
    (HMGB1)
    HMGB1 is associated with progression and metastasis in NSCLC and CRC [50][51].
    CEACAM1 A synergistic antitumor effect has been shown with the simultaneous blockade of TIM-3 and CEACAM1, as well as CEACAM1 and PD-L1 (programmed death-ligand 1), on CRC models [52]. In the early stages of CRC, CEACAM1 inhibits tumor cell proliferation [53]. However, CEACAM1 is a diagnostic and prognostic marker in melanoma, and CEACAM1 is found in tumor samples and sera from patients with pancreatic cancer (PC) and is overexpressed in advanced stages of CRC, NSCLC, and other cancers [54].
    LAG-3 It has been shown that the therapeutic use of PD-1 leads to an increase in the expression level of LAG-3 [55]. In NSCLC, the co-expression of LAG-3 and PD-1 on TILs and PD-L1 on tumor cells is shown [56]. A synergistic effect was observed from the combined use of mAbs binds LAG-3 and PD-1 in various tumor models [57]. MHC class II MHC class II molecule (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 [58].
    Fibrinogen-like protein (FGL-1) The FGL-1/LAG-3 interaction blockade stimulates tumor immunity [59]. The reduced expression of FGL-1 increases the efficiency of CD8+ T-cell activation during LAG-3 blockade [60].
    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 [61][62][63], as well as the association of galectin-3 expression with poor clinical prognosis [64]. However, in melanoma and glioblastoma, the presence of galectin-3 is beneficial for patients [65].
    LSECtin A high level of soluble LSECtin in the blood serum of patients with CRC is associated with the presence of liver metastases [66]. 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 [67].
    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 [68][69]. 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 [68][70][71][72]. 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 [73][74]. The high efficiency of the combined inhibition of PD-1 and CD96 or TIGIT and CD96 has been shown [75]. 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 [76].
    Nectin-4
    (PVRL4)
    Nectin-4 blocking Abs stimulates an NK-mediated antitumor response [77]. 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 [78]. The revealed hyperexpression of nectin-4 by tumor tissues is associated with tumor aggressiveness and poor clinical prognosis [79][80].
    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 [81][82][83]. 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 [82][84].
    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 [32]. 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 [31]. However, the effective suppression of tumor growth was observed only when anti-VISTA mAbs was used in combination with anti-PD-1 mAbs [85][86] or CTLA-4 [87].
    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 ovarian cancer (OC) models highly expressing VISTA [28].
    VSIG-3
    (IGSF11)
    The expression of VSIG-3 by tumor tissues was found in CRC, HCC, and in intestinal-type GC [88]. 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 [89].
    Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [90].
    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 [91].
    Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [90].
    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 [92].
    BTLA The antitumor efficacy of anti-BTLA mAbs has been shown [93][94]. 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 [95]. An increase in median OS [96], as well as the enhancing T-cell proliferation and cytokine production, was observed with the combination of anti-BTLA and anti-PD-1 therapies [97]. HVEM
    (TNFRSF14)
    T-cell activation is observed as a result of HVEM suppression in OC cells and in the ESCC cell line [98][99].
    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 [99][100][101][102][103]. 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 [104]. In GC, an overexpression of BTLA and HVEM is associated with a poor clinical prognosis [105].
    Data on current clinical trials utilizing the considered immune checkpoints are presented in Table 2.
    Table 2. Summary of ongoing clinical trials of receptor inhibitors.
     
    Target Drug Number of Current Trials/
    Phase
    Type of Tumor Some Published Results of Clinical Trials
    Trial Clinical Safety and Efficacy
    TIM-3 Sabatolimab
    (MBG453)
    16
    I, II, III
    Advanced or metastatic
    solid tumors
    Bone marrow diseases
    Glioblastoma
    Hematologic malignancies
    NCT02608268
    Phase I-Ib/II
    Patients received sabatolimab (n = 133)
    or sabatolimab plus spartalizumab (n = 86).
    The MTD was not reached. No responses were
    seen with sabatolimab. Five patients receiving combination treatment had
    PR (6%; lasting 12–27 months) [106]
    TSR-022 4
    I, II
    Advanced or metastatic solid tumors
    Melanoma
    NCT02817633
    Phase I
    In the group of 20 patients who received
    the TSR-022+TSR-042 combination, the ORR
    was 15% (3/20), and disease stabilization
    reached 40% (8/20) [107].
    LY3321367 1
    I
    Solid tumors NCT03099109
    Phase I
    No DLTs were observed in the monotherapy
    (n = 30) or combination (n = 28) therapy. LY3321367 treatment-related adverse events (TRAEs) occurred in ≥2 patients.
    In the NSCLC monotherapy expansion cohort, outcomes varied: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, DCR 35%, PFS 1.9 months] versus anti-PD-1/L1 responders
    (n = 14, ORR 7%, DCR 50%, PFS 7.3 months).
    In combination expansion cohorts (n = 91),
    ORR and DCR were 4% and 42% [108]
    LY3415244,
    BsAb for
    PD-L1/TIM-3
    1
    I
    Advanced solid tumors NCT03752177
    Phase Ia/Ib
    Two patients (16.7%) developed
    clinically significant anaphylactic
    infusion-related reactions.
    One patient with PD-1 refractory NSCLC
    had a near partial response (−29.6%) [109]
    INCAGN02390 5
    I
    Solid tumors
    Melanoma
    - -
    BGB-A425 1
    I
    Advanced or metastatic solid tumors - -
    BMS-986258 1
    I
    Advanced cancer - -
    SHR-1702 2
    I
    Hematologic malignancies Advanced solid tumors - -
    RO7121661,
    BsAb for
    PD-1/TIM-3
    2
    I, II
    Advanced or metastatic solid tumors
    Melanoma
    - -
    LAG-3 Eftilagimod alpha (IMP321) 14
    I, II
    Advanced or metastatic solid tumors
    Melanoma
    NCT00732082
    Phase I
    None of the 6 patients received
    0.5 mg IMP321 experienced TRAEs.
    Of the 5 patients who received IMP321
    at the 2 mg dose level, 1 experienced rash,
    1 reported hot flashes, and 2 had mild pain
    at the injection sites [110]
    NCT00349934
    Phase I
    Thirty patients received IMP321 in three cohorts
    (doses: 0.25, 1.25 and 6.25 mg).
    Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Additionally, t he ORR of 50% compared favorably
    to the 25% rate reported
    in the historical control group [111].
    Favezelimab
    (MK-4280)
    10
    I, II, III
    Advanced or metastatic solid tumors
    Hematologic malignancies
    Melanoma
    NCT03598608
    Phase I/II
    Fifteen patients received MK-4280 with pembrolizumab, four of whom
    achieved a partial response [112]
    Relatlimab
    (BMS-986016)
    31
    I, II
    Advanced or metastatic solid tumors
    Hematologic malignancies
    Melanoma
    NCT01968109
    Phase I/IIa
    Patients received relatlimab + nivolumab.
    In 61 efficacy-evaluable patients, ORR was 11.5% (1 complete, 6 partial (1 unconfirmed) responses); DCR was 49%. Median DOR was not reached (min [0.1þ], max [39.3þ]). ORR was 3.5-fold higher in patients with LAG-3 expression, 1% vs. <1%, regardless of PD-L1 expression. TRAEs occurred in 41%
    (gr 3/4, 4.4%; DC, 1.5%) [113]
    NCT03470922
    Phase II
    The median PFS was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab–nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; p = 0.006 by the log-rank test). PFS at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab–nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Grade 3 or 4 TRAEs occurred in 18.9% of patients in the relatlimab–nivolumab group and in 9.7% of patients in the nivolumab group [114].
    TSR-033 2
    I
    Advanced solid tumors - -
    REGN3767 5
    I, II, III
    Advanced solid tumors - -
    Ieramilimab (LAG525) 5
    I, II
    Advanced solid tumors
    Hematologic malignancies
    Melanoma
    NCT02460224
    Phase I/II
    Patients received fermilab (n = 134)
    or fermilab + spartalizumab (n = 121).
    Four patients experienced DLT in each treatment arm. No MTD was reached. TRAEs occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively.
    Seven patients experienced SAEs in the single-agent (5%) and combination groups (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) CR and 10 (8%) PR.
    In the combination arm, 8 patients (6.6%) experienced SD for 6 months or longer versus 6 patients (4.5%) in the single-agent arm [115]
    FS118,
    BsAb for LAG-3/PD-L1
    1
    I, II
    Advanced solid tumors
    Hematologic malignancies
    Melanoma
    - -
    RO7247669, BsAb for
    LAG-3/PD-1
    5
    I, II
    Advanced or metastatic solid tumors
    Melanoma
    - -
    TIGIT Vibostolimab
    (MK-7684)
    15
    I, II, III
    Advanced or metastatic solid tumors
    Melanoma
    Hematologic malignancies
    NCT02964013
    Phase I
    Part A: 56% of patients receiving monotherapy and 62% receiving a combination of vibostolimab with pembrolizumab had TRAEs. Grade 3–4 TRAEs occurred in 9% and 17% of patients, respectively. No DLT was reported. The confirmed ORR was 0% for monotherapy and 7% for combination therapy.
    Part B: 39 patients had anti-PD-1/PD-L1-naive NSCLC, and all received combination therapy. TRAEs occurred in 85% of patients. The confirmed ORR was 26%, with responses observed in both PD-L1-positive and PD-L1-negative tumors. Sixty-seven had anti-PD-1/PD-L1-refractory NSCLC, and 56% receiving monotherapy and 70% receiving combination therapy had TRAEs. The confirmed ORR was 3% for monotherapy and 3% for combination therapy [116]
    BMS-986207 4
    I, II
    Advanced solid tumors
    Multiple myeloma
    - -
    Etigilimab
    (OMP-313M32)
    2
    I, II
    Advanced or metastatic solid tumors NCT03119428
    Phase Ia/Ib
    Thirty-three patients were enrolled (Phase Ia, n = 23;
    Phase Ib, n = 10). There was no DLT. MTD was not determined. Six patients experienced grade ≥ 3 TRAEs. In Phase Ia, 7 patients (30.0%) had stable disease. In Phase Ib, 1 patient had a PR; 1 patient had prolonged SD of nearly 8 months.
    Median PFS was 56.0 days (Phase Ia)
    and 57.5 days (Phase Ib) [117]
    Tiragolumab 38
    I, II, III
    Advanced or metastatic solid tumors
    Melanoma
    Hematologic malignancies
    NCT02864992
    Phase II
    The RR by independent review was 46%
    (95% CI, 36 to 57), with a median DoR of 11.1 months (95% CI, 7.2 to could not be estimated)
    in the combined-biopsy group. The RR was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed RR was 56% (95% CI, 45 to 66). TRAEs of grade ≥ 3 were reported in 28% [118]
    NCT03563716
    Phase II
    Patients were randomly assigned to receive tiragolumab + atezolizumab (67 (50%))
    or placebo + atezolizumab (68 (50%)). After a median follow-up of 5.9 months
    (4.6–7.6, in the intention-to-treat population,
    21 patients (31.3% [95% CI 19.5–43.2]) in the tiragolumab + atezolizumab group versus
    11 patients (16.2% [6.7–25.7]) in the placebo + atezolizumab group had an
    objective response (p = 0.031).
    Median PFS was 5.4 months (95% CI 4.2-not estimable) in the tiragolumab + atezolizumab group versus 3·6 months (2.7–4.4) in the placebo + atezolizumab group (stratified hazard ratio 0.57 [95% CI 0.37–0.90], p = 0.015).
    Fourteen (21%) patients receiving tiragolumab + atezolizumab and 12 (18%) patients receiving placebo + atezolizumab had SAEs [119]
    Domvanalimab
    (AB154)
    9
    I, II, III
    Advanced or metastatic solid tumors
    Melanoma
    Glioblastoma
    - -
    ASP8374 3
    I
    Advanced solid tumors
    Glioblastoma
    - -
    VISTA CI-8993 1
    I
    Solid tumors - -
    CA-170, VISTA/PD-L1/2 antagonist 2
    I, II
    Advanced or metastatic solid tumors
    lymphomas
    NCT02812875
    Phase I
    According to the RECIST, 33 out of 50 patients who received CA-170 showed SD. PR or CR was not achieved. Severe (grade 3 and 4) TRAEs were observed in 5 patients. No DLTs were observed [85].
    JNJ-61610588 1
    I
    Advanced or metastatic solid tumors - -
    BTLA TAB004/JS004 7
    I, II
    Recurrent/
    refractory malignant lymphoma
    Advanced or metastatic solid tumors
    -

    References

    1. He, Y.; Cao, J.; Zhao, C.; Li, X.; Zhou, C.; Hirsch, F. TIM-3, a Promising Target for Cancer Immunotherapy. OncoTargets Ther. 2018, 11, 7005–7009.
    2. Sánchez-Fueyo, A.; Tian, J.; Picarella, D.; Domenig, C.; Zheng, X.X.; Sabatos, C.A.; Manlongat, N.; Bender, O.; Kamradt, T.; Kuchroo, V.K.; et al. Tim-3 Inhibits T Helper Type 1–Mediated Auto- and Alloimmune Responses and Promotes Immunological Tolerance. Nat. Immunol. 2003, 4, 1093–1101.
    3. Du, W.; Yang, M.; Turner, A.; Xu, C.; Ferris, R.; Huang, J.; Kane, L.; Lu, B. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. Int. J. Mol. Sci. 2017, 18, 645.
    4. Avery, L.; Filderman, J.; Szymczak-Workman, A.L.; Kane, L.P. Tim-3 Co-Stimulation Promotes Short-Lived Effector T Cells, Restricts Memory Precursors, and Is Dispensable for T Cell Exhaustion. Proc. Natl. Acad. Sci. USA 2018, 115, 2455–2460.
    5. Phong, B.L.; Avery, L.; Sumpter, T.L.; Gorman, J.V.; Watkins, S.C.; Colgan, J.D.; Kane, L.P. Tim-3 Enhances Fc ε RI-Proximal Signaling to Modulate Mast Cell Activation. J. Exp. Med. 2015, 212, 2289–2304.
    6. Hendry, S.; Salgado, R.; Gevaert, T.; Russell, P.A.; John, T.; Thapa, B.; Christie, M.; Van De Vijver, K.; Estrada, M.V.; Gonzalez-Ericsson, P.I.; et al. Assessing Tumor Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinom. Adv. Anat. Pathol. 2017, 24, 311.
    7. Fourcade, J.; Sun, Z.; Benallaoua, M.; Guillaume, P.; Luescher, I.F.; Sander, C.; Kirkwood, J.M.; Kuchroo, V.; Zarour, H.M. Upregulation of Tim-3 and PD-1 Expression Is Associated with Tumor Antigen—Specific CD8+ T Cell Dysfunction in Melanoma Patients. J. Exp. Med. 2010, 207, 2175–2186.
    8. Yan, J.; Zhang, Y.; Zhang, J.; Liang, J.; Li, L.; Zheng, L. Tim-3 Expression Defines Regulatory T Cells in Human Tumors. PLoS ONE 2013, 8, e58006.
    9. Pagliano, O.; Morrison, R.M.; Chauvin, J.; Banerjee, H.; Davar, D.; Ding, Q.; Tanegashima, T.; Gao, W.; Chakka, S.R.; Deblasio, R.; et al. Tim-3 Mediates T Cell Trogocytosis to Limit Antitumor Immunity. J. Clin. Investig. 2022, 132, 1–15.
    10. Workman, C.J.; Vignali, D.A.A. The CD4-Related Molecule, LAG-3 (CD223), Regulates the Expansion of Activated T Cells. Eur. J. Immunol. 2003, 33, 970–979.
    11. Macon-Lemaitre, L.; Triebel, F. The Negative Regulatory Function of the Lymphocyte-Activation Gene-3 Co-Receptor (CD223) on Human T Cells. Immunology 2005, 115, 170–178.
    12. Liang, B.; Workman, C.; Lee, J.; Chew, C.; Dale, B.M.; Colonna, L.; Flores, M.; Li, N.; Schweighoffer, E.; Greenberg, S.; et al. Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II. J. Immunol. 2008, 180, 5916–5926.
    13. Roy, S.; Coulon, P.-G.; Srivastava, R.; Vahed, H.; Kim, G.J.; Walia, S.S.; Yamada, T.; Fouladi, M.A.; Ly, V.T.; BenMohamed, L. Blockade of LAG-3 Immune Checkpoint Combined with Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-Viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease. Front. Immunol. 2018, 9, 2922.
    14. Maruhashi, T.; Sugiura, D. LAG-3: From Molecular Functions to Clinical Applications. J. Immunother. Cancer 2020, 8, e001014.
    15. Li, N.; Wang, Y.; Forbes, K.; Vignali, K.M.; Heale, B.S.; Saftig, P.; Hartmann, D.; Black, R.A.; Rossi, J.J.; Blobel, C.P.; et al. Metalloproteases Regulate T-Cell Proliferation and Effector Function via LAG-3. EMBO J. 2007, 26, 494–504.
    16. Long, L.; Zhang, X.; Chen, F.; Pan, Q.; Phiphatwatchara, P.; Zeng, Y.; Chen, H. The Promising Immune Checkpoint LAG-3: From Tumor Microenvironment to Cancer Immunotherapy. Genes Cancer 2018, 9, 176–189.
    17. Maeda, T.K.; Sugiura, D.; Okazaki, I.M.; Maruhashi, T.; Okazaki, T. Atypical Motifs in the Cytoplasmic Region of the Inhibitory Immune Co-Receptor LAG-3 Inhibit T Cell Activation. J. Biol. Chem. 2019, 294, 6017–6026.
    18. Stanietsky, N.; Simic, H.; Arapovic, J.; Toporik, A.; Levy, O.; Novik, A.; Levine, Z.; Beiman, M.; Dassa, L.; Achdout, H.; et al. The Interaction of TIGIT with PVR and PVRL2 Inhibits Human NK Cell Cytotoxicity. Proc. Natl. Acad. Sci. USA 2009, 106, 17858–17863.
    19. Bi, J.; Zheng, X.; Chen, Y.; Wei, H.; Sun, R.; Tian, Z. TIGIT Safeguards Liver Regeneration through Regulating Natural Killer Cell-Hepatocyte Crosstalk. Hepatology 2014, 60, 1389–1398.
    20. Anderson, A.C.; Joller, N.; Kuchroo, V.K. Lag-3, Tim-3, and TIGIT: Co-Inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016, 44, 989–1004.
    21. Harjunpää, H.; Guillerey, C. TIGIT as an Emerging Immune Checkpoint. Clin. Exp. Immunol. 2020, 200, 108–119.
    22. Joller, N.; Hafler, J.P.; Brynedal, B.; Kassam, N.; Spoerl, S.; Levin, S.D.; Sharpe, A.H.; Kuchroo, V.K. Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions. J. Immunol. 2011, 186, 1338–1342.
    23. El Tanbouly, M.A.; Croteau, W.; Noelle, R.J.; Lines, J.L. VISTA: A Novel Immunotherapy Target for Normalizing Innate and Adaptive Immunity. Semin. Immunol. 2019, 42, 101308.
    24. Wang, G.; Tai, R.; Wu, Y.; Yang, S.; Wang, J.; Yu, X.; Lei, L.; Shan, Z.; Li, N. The Expression and Immunoregulation of Immune Checkpoint Molecule VISTA in Autoimmune Diseases and Cancers. Cytokine Growth Factor Rev. 2020, 52, 1–14.
    25. Hernandez-Martinez, J.M.; Vergara, E.; Zatarain-Barrón, Z.L.; Barrón-Barrón, F.; Arrieta, O. Vista/PD-1H: A Potential Target for Non-Small Cell Lung Cancer Immunotherapy. J. Thorac. Dis. 2018, 10, 6378–6382.
    26. Zhang, M.; Pang, H.J.; Zhao, W.; Li, Y.F.; Yan, L.X.; Dong, Z.Y.; He, X.F. VISTA Expression Associated with CD8 Confers a Favorable Immune Microenvironment and Better Overall Survival in Hepatocellular Carcinoma. BMC Cancer 2018, 18, 1–8.
    27. Mulati, K.; Hamanishi, J.; Matsumura, N.; Chamoto, K.; Mise, N.; Abiko, K.; Baba, T.; Yamaguchi, K.; Horikawa, N.; Murakami, R.; et al. VISTA Expressed in Tumour Cells Regulates T Cell Function. Br. J. Cancer 2019, 120, 115–127.
    28. Huang, X.; Zhang, X.; Li, E.; Zhang, G.; Wang, X.; Tang, T.; Bai, X.; Liang, T. VISTA: An Immune Regulatory Protein Checking Tumor and Immune Cells in Cancer Immunotherapy. J. Hematol. Oncol. 2020, 13, 1–13.
    29. Le Mercier, I.; Chen, W.; Lines, J.L.; Day, M.; Li, J.; Sergent, P.; Noelle, R.J.; Wang, L. VISTA Is an Immune Checkpoint Molecule for Human T Cells. Cancer Res. 2014, 74, 1924–1932.
    30. Flies, D.B.; Han, X.; Higuchi, T.; Zheng, L.; Sun, J.; Ye, J.J.; Chen, L. Coinhibitory Receptor PD-1H Preferentially Suppresses CD4+ T Cell-Mediated Immunity. J. Clin. Investig. 2014, 124, 1966–1975.
    31. Le Mercier, I.; Chen, W.; Lines, J.L.; Day, M.; Li, J.; Sergent, P.; Noelle, R.J.; Wang, L. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res. 2014, 74, 1933–1944.
    32. Xu, W.; Dong, J.; Zheng, Y.; Zhou, J.; Yuan, Y.; Minh, H.; Miller, H.E.; Olson, M.; Rajasekaran, K.; Ernstoff, M.S.; et al. Immune-Checkpoint Protein Vista Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression. Cancer Immunol. Res. 2019, 7, 1497–1510.
    33. Serriari, N.-E.; Gondois-Rey, F.; Guillaume, Y.; Remmerswaal, E.B.M.; Pastor, S.; Messal, N.; Truneh, A.; Hirsch, I.; van Lier, R.A.W.; Olive, D. B and T Lymphocyte Attenuator Is Highly Expressed on CMV-Specific T Cells during Infection and Regulates Their Function. J. Immunol. 2010, 185, 3140–3148.
    34. Del Rio, M.L.; Kaye, J.; Rodriguez-Barbosa, J.I. Detection of Protein on BTLA low Cells and in Vivo Antibody-Mediated down-Modulation of BTLA on Lymphoid and Myeloid Cells of C57BL/6 and BALB/c BTLA Allelic Variants. Immunobiology 2010, 215, 570–578.
    35. Paulos, C.M.; June, C.H. Putting the Brakes on BTLA in T Cell-Mediated Cancer Immunotherapy. J. Clin. Investig. 2010, 120, 76–80.
    36. Hwang, H.J.; Lee, J.J.; Kang, S.H.; Suh, J.K.; Choi, E.S.; Jang, S.; Hwang, S.H.; Koh, K.N.; Im, H.J.; Kim, N. The BTLA and PD-1 Signaling Pathways Independently Regulate the Proliferation and Cytotoxicity of Human Peripheral Blood Γδ T Cells. Immun. Inflamm. Dis. 2021, 9, 274–287.
    37. Zhao, Y.; Niu, C.; Cui, J. Gamma-Delta (Γδ) T Cells: Friend or Foe in Cancer Development. J. Transl. Med. 2018, 16, 3.
    38. Wang, Q.; Zhang, J.; Tu, H.; Liang, D.; Chang, D.W.; Ye, Y.; Wu, X. Soluble Immune Checkpoint-Related Proteins as Predictors of Tumor Recurrence, Survival, and T Cell Phenotypes in Clear Cell Renal Cell Carcinoma Patients. J. Immunother. Cancer 2019, 7, 334.
    39. Bian, B.; Fanale, D.; Dusetti, N.; Roque, J.; Pastor, S.; Chretien, A.S.; Incorvaia, L.; Russo, A.; Olive, D.; Iovanna, J. Prognostic Significance of Circulating PD-1, PD-L1, Pan-BTN3As, BTN3A1 and BTLA in Patients with Pancreatic Adenocarcinoma. Oncoimmunology 2019, 8, e1561120.
    40. Wang, Q.; Ye, Y.; Yu, H.; Lin, S.H.; Tu, H.; Liang, D.; Chang, D.W.; Huang, M.; Wu, X. Immune Checkpoint-Related Serum Proteins and Genetic Variants Predict Outcomes of Localized Prostate Cancer, a Cohort Study. Cancer Immunol. Immunother. 2021, 70, 701–712.
    41. Gorgulho, J.; Roderburg, C.; Heymann, F.; Schulze-Hagen, M.; Beier, F.; Vucur, M.; Kather, J.N.; Laleh, N.G.; Tacke, F.; Brümmendorf, T.H.; et al. Serum Levels of Soluble B and T Lymphocyte Attenuator Predict Overall Survival in Patients Undergoing Immune Checkpoint Inhibitor Therapy for Solid Malignancies. Int. J. Cancer 2021, 149, 1189–1198.
    42. Ngiow, S.F.; von Scheidt, B.; Akiba, H.; Yagita, H.; Teng, M.W.L.; Smyth, M.J. Anti-TIM3 Antibody Promotes T Cell IFN—Mediated Antitumor Immunity and Suppresses Established Tumors. Cancer Res. 2011, 71, 3540–3551.
    43. Koyama, S.; Akbay, E.A.; Li, Y.Y.; Herter-Sprie, G.S.; Buczkowski, K.A.; Richards, W.G.; Gandhi, L.; Redig, A.J.; Rodig, S.J.; Asahina, H.; et al. Adaptive Resistance to Therapeutic PD-1 Blockade Is Associated with Upregulation of Alternative Immune Checkpoints. Nat. Commun. 2016, 7, 10501.
    44. Zhou, G.; Sprengers, D.; Boor, P.P.C.; Doukas, M.; Schutz, H.; Mancham, S.; Pedroza-Gonzalez, A.; Polak, W.G.; de Jonge, J.; Gaspersz, M.; et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology 2017, 153, 1107–1119.e10.
    45. Limagne, E.; Richard, C.; Thibaudin, M.; Fumet, J.D.; Truntzer, C.; Lagrange, A.; Favier, L.; Coudert, B.; Ghiringhelli, F. Tim-3/Galectin-9 Pathway and MMDSC Control Primary and Secondary Resistances to PD-1 Blockade in Lung Cancer Patients. Oncoimmunology 2019, 8, e1564505-13.
    46. Yasinska, I.M.; Sakhnevych, S.S.; Pavlova, L.; Selnø, A.T.H.; Abeleira, A.M.T.; Benlaouer, O.; Silva, I.G.; Mosimann, M.; Varani, L.; Bardelli, M.; et al. The TiM-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer. Front. Immunol. 2019, 10, 594.
    47. Curley, J.; Conaway, M.R.; Chinn, Z.; Duska, L.; Stoler, M.; Mills, A.M. Looking Past PD-L1: Expression of Immune Checkpoint TIM-3 and Its Ligand Galectin-9 in Cervical and Vulvar Squamous Neoplasia. Mod. Pathol. 2020, 33, 1182–1192.
    48. Zhou, X.; Sun, L.; Jing, D.; Xu, G.; Zhang, J.; Lin, L.; Zhao, J.; Yao, Z.; Lin, H. Galectin-9 Expression Predicts Favorable Clinical Outcome in Solid Tumors: A Systematic Review and Meta-Analysis. Front. Physiol. 2018, 9, 452.
    49. Yang, R.; Sun, L.; Li, C.F.; Wang, Y.H.; Yao, J.; Li, H.; Yan, M.; Chang, W.C.; Hsu, J.M.; Cha, J.H.; et al. Galectin-9 Interacts with PD-1 and TIM-3 to Regulate T Cell Death and is a Target for Cancer Immunotherapy. Nat. Commun. 2021, 12, 832.
    50. Wu, L.; Yang, L. The Function and Mechanism of HMGB1 in Lung Cancer and Its Potential Therapeutic Implications. Oncol. Lett. 2018, 15, 6799–6805.
    51. Cheng, K.J.; Alshawsh, M.A.; Mejia Mohamed, E.H.; Thavagnanam, S.; Sinniah, A.; Ibrahim, Z.A. HMGB1: An Overview of Its Versatile Roles in the Pathogenesis of Colorectal Cancer. Cell. Oncol. 2020, 43, 177–193.
    52. Huang, Y.-H.; Zhu, C.; Kondo, Y.; Anderson, A.C.; Gandhi, A.; Russell, A.; Dougan, S.K.; Petersen, B.-S.; Melum, E.; Pertel, T.; et al. CEACAM1 Regulates TIM-3-Mediated Tolerance and Exhaustion. Nature 2015, 517, 386–390.
    53. Dankner, M.; Gray-Owen, S.D.; Huang, Y.H.; Blumberg, R.S.; Beauchemin, N. CEACAM1 as a Multi-Purpose Target for Cancer Immunotherapy. Oncoimmunology 2017, 6, e1328336.
    54. Calinescu, A.; Turcu, G.; Nedelcu, R.I.; Brinzea, A.; Hodorogea, A.; Antohe, M.; Diaconu, C.; Bleotu, C.; Pirici, D.; Jilaveanu, L.B.; et al. On the Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) in Human Malignancies. J. Immunol. Res. 2018, 2018, 7169081.
    55. Zelba, H.; Bedke, J.; Hennenlotter, J.; Mostböck, S.; Zettl, M.; Zichner, T.; Chandran, A.; Stenzl, A.; Rammensee, H.G.; Gouttefangeas, C. PD-1 and LAG-3 Dominate Checkpoint Receptor-Mediated T-Cell Inhibition in Renal Cell Carcinoma. Cancer Immunol. Res. 2019, 7, 1891–1899.
    56. He, Y.; Yu, H.; Rozeboom, L.; Rivard, C.J.; Ellison, K.; Dziadziuszko, R.; Suda, K.; Ren, S.; Wu, C.; Hou, L.; et al. LAG-3 Protein Expression in Non–Small Cell Lung Cancer and Its Relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes. J. Thorac. Oncol. 2017, 12, 814–823.
    57. Chen, X.; Song, X.; Li, K.; Zhang, T. FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy. Front. Immunol. 2019, 10, 292.
    58. Axelrod, M.L.; Cook, R.S.; Johnson, D.B.; Balko, J.M. Biological Consequences of MHC-II Expression by Tumor Cells in Cancer. Clin. Cancer Res. 2019, 25, 2392–2402.
    59. Chen, Y.; Zhu, G.; Yin, W.; Zheng, L.; Zhou, T.; Badri, T. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG3. Cell 2020, 176, 334–347.
    60. Wang, J.; Wei, W.; Tang, Q.; Lu, L.; Luo, Z.; Li, W.; Lu, Y.; Pu, J. Oxysophocarpine Suppresses Hepatocellular Carcinoma Growth and Sensitizes the Therapeutic Blockade of Anti-Lag-3 via Reducing FGL1 Expression. Cancer Med. 2020, 9, 7125–7136.
    61. Nangia-Makker, P.; Hogan, V.; Raz, A. Galectin-3 and Cancer Stemness. Glycobiology 2018, 28, 172–181.
    62. Chen, C.; Duckworth, C.A.; Zhao, Q.; Pritchard, D.M.; Rhodes, J.M.; Yu, L.G. Increased Circulation of Galectin-3 in Cancer Induces Secretion of Metastasis-Promoting Cytokines from Blood Vascular Endothelium. Clin. Cancer Res. 2013, 19, 1693–1704.
    63. Tanida, S.; Mori, Y.; Ishida, A.; Akita, K.; Nakada, H. Galectin-3 Binds to MUC1-N-Terminal Domain and Triggers Recruitment of β-Catenin in MUC1-Expressing Mouse 3T3 Cells. Biochim. Biophys. Acta Gen. Subj. 2014, 1840, 1790–1797.
    64. Wang, C.; Zhou, X.; Ma, L.; Zhuang, Y.; Wei, Y.; Zhang, L.; Jin, S.; Liang, W.; Shen, X.; Li, C.; et al. Galectin-3 May Serve as a Marker for Poor Prognosis in Colorectal Cancer: A Meta-Analysis. Pathol. Res. Pract. 2019, 215, 152612.
    65. Ruvolo, P.P. Galectin 3 as a Guardian of the Tumor Microenvironment. Biochim. Biophys. Acta Mol. Cell Res. 2016, 1863, 427–437.
    66. Zuo, Y.; Ren, S.; Wang, M.; Liu, B.; Yang, J.; Kuai, X.; Lin, C.; Zhao, D.; Tang, L.; He, F. Novel Roles of Liver Sinusoidal Endothelial Cell Lectin in Colon Carcinoma Cell Adhesion, Migration and in-Vivo Metastasis to the Liver. Gut 2013, 62, 1169–1178.
    67. Xu, F.; Liu, J.; Liu, D.; Liu, B.; Wang, M.; Hu, Z.; Du, X.; Tang, L.; He, F. LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-Cell Responses. Cancer Res. 2014, 74, 3418–3428.
    68. Zhang, Q.; Bi, J.; Zheng, X.; Chen, Y.; Wang, H.; Wu, W.; Wang, Z.; Wu, Q.; Peng, H.; Wei, H.; et al. Blockade of the Checkpoint Receptor TIGIT Prevents NK Cell Exhaustion and Elicits Potent Anti-Tumor Immunity. Nat. Immunol. 2018, 19, 723–732.
    69. Han, D.; Xu, Y.; Zhao, X.; Mao, Y.; Kang, Q.; Wen, W.; Yu, X.; Xu, L.; Liu, F.; Zhang, M.; et al. A Novel Human Anti-TIGIT Monoclonal Antibody with Excellent Function in Eliciting NK Cell-Mediated Antitumor Immunity. Biochem. Biophys. Res. Commun. 2021, 534, 134–140.
    70. Dixon, K.O.; Schorer, M.; Nevin, J.; Etminan, Y.; Kondo, T.; Kurtulus, S.; Kassam, N.; Sobel, R.A.; Jain, R.K.; Anderson, A.C.; et al. Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Anti-Tumor Immunity. HHS Public Access 2018, 200, 3000–3007.
    71. Hansen, K.; Kumar, S.; Logronio, K.; Whelan, S.; Qurashi, S.; Cheng, H.-Y.; Drake, A.; Tang, M.; Wall, P.; Bernados, D.; et al. COM902, a Novel Therapeutic Antibody Targeting TIGIT Augments Anti-Tumor T Cell Function in Combination with PVRIG or PD-1 Pathway Blockade. Cancer Immunol. Immunother. 2021, 70, 3525–3540.
    72. Martinez, M.; Kim, S.; Jean, N.S.; O’Brien, S.; Lian, L.; Sun, J.; Verona, R.I.; Moon, E. Addition of Anti-TIM3 or Anti-TIGIT Antibodies to Anti-PD1 Blockade Augments Human T Cell Adoptive Cell Transfer. Oncoimmunology 2021, 10, 1873607.
    73. Preillon, J.; Cuende, J.; Rabolli, V.; Garnero, L.; Mercier, M.; Wald, N.; Pappalardo, A.; Denies, S.; Jamart, D.; Michaux, A.C.; et al. Restoration of T-Cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-Tigit Antagonist Antibodies. Mol. Cancer Ther. 2021, 20, 121–131.
    74. Ge, Z.; Zhou, G.; Campos Carrascosa, L.; Gausvik, E.; Boor, P.P.C.; Noordam, L.; Doukas, M.; Polak, W.G.; Terkivatan, T.; Pan, Q.; et al. TIGIT and PD1 Co-Blockade Restores Ex Vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma. Cell. Mol. Gastroenterol. Hepatol. 2021, 12, 443–464.
    75. Harjunpää, H.; Blake, S.J.; Ahern, E.; Allen, S.; Liu, J.; Yan, J.; Lutzky, V.; Takeda, K.; Aguilera, A.R.; Guillerey, C.; et al. Deficiency of Host CD96 and PD-1 or TIGIT Enhances Tumor Immunity without Signi Fi Cantly Compromising Immune Homeostasis. Oncoimmunology 2018, 7, e1445949.
    76. Gorvel, L.; Olive, D. Targeting the “PVR-TIGIT Axis” with Immune Checkpoint Therapies. F1000Research 2020, 9, 354.
    77. Reches, A.; Ophir, Y.; Stein, N.; Kol, I.; Isaacson, B.; Charpak Amikam, Y.; Elnekave, A.; Tsukerman, P.; Kucan Brlic, P.; Lenac, T.; et al. Nectin4 Is a Novel TIGIT Ligand Which Combines Checkpoint Inhibition and Tumor Specificity. J. Immunother. Cancer 2020, 8, 1–9.
    78. Nayak, A.; Nayak, D.; Sethy, C. Nectin-4 Is a Breast Cancer Stem Cell Marker That Induces WNT/β-Catenin Signaling via Pi3k/Akt Axis. Int. J. Biochem. Cell Biol. 2017, 89, 85–94.
    79. Sethy, C.; Goutam, K.; Nayak, D.; Pradhan, R.; Molla, S.; Chatterjee, S.; Rout, N.; Wyatt, M.D.; Narayan, S.; Kundu, C.N. Clinical Significance of a Pvrl 4 Encoded Gene Nectin-4 in Metastasis and Angiogenesis for Tumor Relapse. J. Cancer Res. Clin. Oncol. 2020, 146, 245–259.
    80. Deng, H.; Shi, H.; Chen, L.; Zhou, Y.; Jiang, J. Over-Expression of Nectin-4 Promotes Progression of Esophageal Cancer and Correlates with Poor Prognosis of the Patients. Cancer Cell Int. 2019, 19, 106.
    81. Molfetta, R.; Zitti, B.; Lecce, M.; Milito, N.D.; Stabile, H.; Fionda, C.; Cippitelli, M.; Gismondi, A.; Santoni, A.; Paolini, R. CD155: A Multi-Functional Molecule in Tumor Progression. Int. J. Mol. Sci. 2020, 21, 922.
    82. Zhao, K.; Ma, L.; Feng, L.; Huang, Z.; Meng, X.; Yu, J. CD155 Overexpression Correlates with Poor Prognosis in Primary Small Cell Carcinoma of the Esophagus. Front. Mol. Biosci. 2021, 7, 608404.
    83. Nishiwada, S.; Sho, M.; Yasuda, S.; Shimada, K.; Yamato, I.; Akahori, T.; Kinoshita, S.; Nagai, M.; Konishi, N.; Nakajima, Y. Clinical Significance of CD155 Expression in Human Pancreatic Cancer. Anticancer Res. 2015, 2298, 2287–2297.
    84. Sun, Y.; Luo, J.; Chen, Y.; Cui, J.; Lei, Y.; Cui, Y.; Jiang, N. Combined Evaluation of the Expression Status of CD155 and TIGIT Plays an Important Role in the Prognosis of LUAD (Lung Adenocarcinoma). Int. Immunopharmacol. 2020, 80, 106198.
    85. Huang, R.Y.; Eppolito, C.; Lele, S.; Shrikant, P.; Matsuzaki, J.; Odunsi, K. LAG3 and PD1 Co-Inhibitory Molecules Collaborate to Limit CD8+ T Cell Signaling and Dampen Antitumor Immunity in a Murine Ovarian Cancer Model. Oncotarget 2015, 6, 27359–27377.
    86. Burugu, S.; Dancsok, A.R.; Nielsen, T.O. Emerging Targets in Cancer Immunotherapy. Semin. Cancer Biol. 2018, 52, 39–52.
    87. Gao, J.; Ward, J.F.; Pettaway, C.A.; Shi, L.Z.; Subudhi, S.K.; Vence, L.M.; Zhao, H.; Chen, J.; Chen, H.; Efstathiou, E.; et al. VISTA Is an Inhibitory Immune Checkpoint That Is Increased after Ipilimumab Therapy in Patients with Prostate Cancer. Nat. Med. 2017, 23, 551–555.
    88. Watanabe, T.; Suda, T.; Tsunoda, T.; Uchida, N.; Ura, K.; Kato, T.; Hasegawa, S.; Satoh, S.; Ohgi, S.; Tahara, H.; et al. Identification of Immunoglobulin Superfamily 11 (IGSF11) as a Novel Target for Cancer Immunotherapy of Gastrointestinal and Hepatocellular Carcinomas. Cancer Sci. 2005, 96, 498–506.
    89. Ghouzlani, A.; Rafii, S.; Karkouri, M.; Lakhdar, A.; Badou, A. The Promising IgSF11 Immune Checkpoint Is Highly Expressed in Advanced Human Gliomas and Associates to Poor Prognosis. Front. Oncol. 2021, 10, 608609.
    90. Mehta, N.; Maddineni, S.; Kelly, R.L.; Lee, R.B.; Hunter, S.A.; Silberstein, J.L.; Parra Sperberg, R.A.; Miller, C.L.; Rabe, A.; Labanieh, L.; et al. An Engineered Antibody Binds a Distinct Epitope and Is a Potent Inhibitor of Murine and Human VISTA. Sci. Rep. 2020, 10, 15171.
    91. Johnston, R.J.; Su, L.J.; Pinckney, J.; Critton, D.; Boyer, E.; Krishnakumar, A.; Corbett, M.; Rankin, A.L.; Dibella, R.; Campbell, L.; et al. VISTA Is an Acidic PH-Selective Ligand for PSGL-1. Nature 2019, 574, 565–570.
    92. Wang, R.; Song, S.; Harada, K.; Ghazanfari Amlashi, F.; Badgwell, B.; Pizzi, M.P.; Xu, Y.; Zhao, W.; Dong, X.; Jin, J.; et al. Multiplex Profiling of Peritoneal Metastases from Gastric Adenocarcinoma Identified Novel Targets and Molecular Subtypes That Predict Treatment Response. Gut 2020, 69, 18–31.
    93. Chen, Y.L.; Lin, H.W.; Chien, C.L.; Lai, Y.L.; Sun, W.Z.; Chen, C.A.; Cheng, W.F. BTLA Blockade Enhances Cancer Therapy by Inhibiting IL-6/IL-10-Induced CD19high B Lymphocytes. J. Immunother. Cancer 2019, 7, 313.
    94. Sekar, D.; Govene, L.; Del Río, M.L.; Sirait-Fischer, E.; Fink, A.F.; Brüne, B.; Rodriguez-Barbosa, J.I.; Weigert, A. Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma. Int. J. Mol. Sci. 2018, 19, 752.
    95. Fourcade, J.; Sun, Z.; Pagliano, O.; Guillaume, P.; Luescher, I.F.; Sander, C.; Kirkwood, J.M.; Olive, D.; Kuchroo, V.; Zarour, H.M. CD8+ T Cells Specific for Tumor Antigens Can Be Rendered Dysfunctional by the Tumor Microenvironment through Upregulation of the Inhibitory Receptors BTLA and PD-1. Cancer Res. 2012, 72, 887–896.
    96. Choi, J.; Medikonda, R.; Saleh, L.; Kim, T.; Pant, A.; Srivastava, S.; Kim, Y.H.; Jackson, C.; Tong, L.; Routkevitch, D.; et al. Combination Checkpoint Therapy with Anti-PD-1 and Anti-BTLA Results in a Synergistic Therapeutic Effect against Murine Glioblastoma. Oncoimmunology 2021, 10, 1956142.
    97. Chevalier, M.F.; Bohner, P.; Pieraerts, C.; Lhermitte, B.; Gourmaud, J.; Nobile, A.; Rotman, S.; Cesson, V.; Martin, V.; Legris, A.S.; et al. Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer. Eur. Urol. 2017, 71, 854–857.
    98. Zhang, T.; Ye, L.; Han, L.; He, Q.; Zhu, J. Knockdown of HVEM, a Lymphocyte Regulator Gene, in Ovarian Cancer Cells Increases Sensitivity to Activated T Cells. Oncol. Res. 2016, 24, 189–196.
    99. Migita, K.; Sho, M.; Shimada, K.; Yasuda, S.; Yamato, I.; Takayama, T.; Matsumoto, S.; Wakatsuki, K.; Hotta, K.; Tanaka, T.; et al. Significant Involvement of Herpesvirus Entry Mediator in Human Esophageal Squamous Cell Carcinoma. Cancer 2014, 120, 808–817.
    100. Sasaki, Y.; Hokuto, D.; Inoue, T.; Nomi, T.; Yoshikawa, T.; Matsuo, Y.; Koyama, F.; Sho, M. Significance of Herpesvirus Entry Mediator Expression in Human Colorectal Liver Metastasis. Ann. Surg. Oncol. 2019, 26, 3982–3989.
    101. Tang, M.; Cao, X.; Li, Y.; Li, G.-Q.; He, Q.-H.; Li, S.-J.; Chen, J.; Xu, G.-L.; Zhang, K.-Q. High Expression of Herpes Virus Entry Mediator Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma. Am. J. Cancer Res. 2019, 9, 975–987.
    102. Yi, Y.; Ni, X.C.; Liu, G.; Yin, Y.R.; Huang, J.L.; Gan, W.; Zhou, P.Y.; Guan, R.Y.; Zhou, C.; Sun, B.Y.; et al. Clinical Significance of Herpes Virus Entry Mediator Expression in Hepatitis B Virus-Related Hepatocellular Carcinoma. Oncol. Lett. 2020, 20, 1–9.
    103. Han, M.Z.; Wang, S.; Zhao, W.B.; Ni, S.L.; Yang, N.; Kong, Y.; Huang, B.; Chen, A.J.; Li, X.G.; Wang, J.; et al. Immune Checkpoint Molecule Herpes Virus Entry Mediator Is Overexpressed and Associated with Poor Prognosis in Human Glioblastoma. EBioMedicine 2019, 43, 159–170.
    104. Carreras, J.; Lopez-Guillermo, A.; Kikuti, Y.Y.; Itoh, J.; Masashi, M.; Ikoma, H.; Tomita, S.; Hiraiwa, S.; Hamoudi, R.; Rosenwald, A.; et al. High TNFRSF14 and Low BTLA Are Associated with Poor Prognosis in Follicular Lymphoma and in Diffuse Large B-Cell Lymphoma Transformation. J. Clin. Exp. Hematop. 2019, 59, 1–16.
    105. Lan, X.; Li, S.; Gao, H.; Nanding, A.; Quan, L.; Yang, C.; Ding, S.; Xue, Y. Increased BTLA and HVEM in Gastric Cancer Are Associated with Progression and Poor Prognosis. OncoTargets Ther. 2017, 10, 919–926.
    106. Curigliano, G.; Gelderblom, H.; Mach, N.; Doi, T.; Tai, D.; Forde, P.M.; Sarantopoulos, J.; Bedard, P.L.; Lin, C.C.; Hodi, F.S.; et al. Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Clin. Cancer Res. 2021, 27, 3620–3629.
    107. Davar, D.; Boasberg; Eroglu, Z.; Falchook, G.; Gainor, J.; Hamilton, E.; Hecht, J.R.; Luke, J.; Pishvaian, M.; Ribas, A.; et al. A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Combination with TSR-042 (Anti-PD-1) in Patients with Colorectal Cancer and Post-PD-1 NSCLC and Melanoma. 2018, pp. 106–107. Available online: https://higherlogicdownload.s3.amazonaws.com/SITCANCER/7aaf41a8-2b65-4783-b86e-d48d26ce14f8/UploadedImages/Annual_Meeting_2018/Annual_Meeting/Abstracts/Abstract_Book_Edited_11_20.pdf (accessed on 12 July 2022).
    108. Harding, J.J.; Moreno, V.; Bang, Y.J.; Hong, M.H.; Patnaik, A.; Trigo, J.; Szpurka, A.M.; Yamamoto, N.; Doi, T.; Fu, S.; et al. Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody. Clin. Cancer Res. 2021, 27, 2168–2178.
    109. Hellmann, M.D.; Bivi, N.; Calderon, B.; Shimizu, T.; Delafontaine, B.; Liu, Z.T.; Szpurka, A.M.; Copeland, V.; Stephen Hodi, F.; Rottey, S.; et al. Safety and Immunogenicity of LY3415244, a Bispecific Antibody against TIM-3 and PD-L1, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2021, 27, 2773–2781.
    110. Wang-Gillam, A.; Plambeck-Suess, S.; Goedegebuure, P.; Simon, P.O.; Mitchem, J.B.; Hornick, J.R.; Sorscher, S.; Picus, J.; Suresh, R.; Lockhart, A.C.; et al. A Phase i Study of IMP321 and Gemcitabine as the Front-Line Therapy in Patients with Advanced Pancreatic Adenocarcinoma. Investig. New Drugs 2013, 31, 707–713.
    111. Brignone, C.; Gutierrez, M.; Mefti, F.; Brain, E.; Jarcau, R.; Cvitkovic, F.; Bousetta, N.; Medioni, J.; Gligorov, J.; Grygar, C.; et al. First-Line Chemoimmunotherapy in Metastatic Breast Carcinoma: Combination of Paclitaxel and IMP321 (LAG-3Ig) Enhances Immune Responses and Antitumor Activity. J. Transl. Med. 2010, 8, 71.
    112. Lakhani, N.; Bauer, T.; Abraham, A.; Luddy, J.; Palcza, J.; Chartash, E.; Healy, J.; Patnaik, A. The Anti–LAG-3 Antibody MK-4280 as Monotherapy and in Combination with Pembrolizumab for Advanced Solid Tumors: First-in-Human Phase 1 Dose-Finding Study. 2018, pp. 113–114. Available online: https://higherlogicdownload.s3.amazonaws.com/SITCANCER/7aaf41a8-2b65-4783-b86e-d48d26ce14f8/UploadedImages/Annual_Meeting_2018/Annual_Meeting/Abstracts/Abstract_Book_Edited_11_20.pdf (accessed on 12 July 2022).
    113. Ascierto, P.A.; Bono, P.; Bhatia, S.; Melero, I.; Nyakas, M.S.; Svane, I.-M.; Larkin, J.; Gomez-Roca, C.; Schadendorf, D.; Dummer, R.; et al. Efficacy of BMS-986016, a Monoclonal Antibody That Targets Lymphocyte Activation Gene-3 (LAG-3), in Combination with Nivolumab in Pts with Melanoma Who Progressed during Prior Anti–PD-1/PD-L1 Therapy (Mel Prior IO) in All-Comer and Biomarker-Enriched Popu. Ann. Oncol. 2017, 28, v611–v612.
    114. Tawbi, H.A.; Schadendorf, D.; Lipson, E.J.; Ascierto, P.A.; Matamala, L.; Castillo Gutiérrez, E.; Rutkowski, P.; Gogas, H.J.; Lao, C.D.; De Menezes, J.J.; et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 2022, 386, 24–34.
    115. Schöffski, P.; Tan, D.S.W.; Martín, M.; Ochoa-De-Olza, M.; Sarantopoulos, J.; Carvajal, R.D.; Kyi, C.; Esaki, T.; Prawira, A.; Akerley, W.; et al. Phase I/II Study of the LAG-3 Inhibitor Ieramilimab (LAG525) ± Anti-PD-1 Spartalizumab (PDR001) in Patients with Advanced Malignancies. J. Immunother. Cancer 2022, 10, e003776.
    116. Niu, J.; Lee, D.H.; Kim, D.; Nagrial, A.; Voskoboynik, M.; Chung, H.C.; Mileham, K. First-in-Human Phase 1 Study of the Anti-TIGIT Antibody Vibostolimab as Monotherapy or with Pembrolizumab for Advanced Solid Tumors. Including. Ann. Oncol. 2022, 33, 169–180.
    117. Mettu, N.B.; Ulahannan, S.V.; Bendell, J.C.; Garrido-Laguna, I.; Strickler, J.H.; Moore, K.N.; Stagg, R.; Kapoun, A.M.; Faoro, L.; Sharma, S. A Phase 1a/b Open-Label, Dose-Escalation Study of Etigilimab Alone or in Combination with Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumors. Clin. Cancer Res. 2022, 28, 882–892.
    118. Paik, P.K.; Felip, E.; Veillon, R.; Sakai, H.; Cortot, A.B.; Garassino, M.C.; Mazieres, J.; Viteri, S.; Senellart, H.; Van Meerbeeck, J.; et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N. Engl. J. Med. 2020, 383, 931–943.
    119. Cho, B.C.; Abreu, D.R.; Hussein, M.; Cobo, M.; Patel, A.J.; Secen, N.; Lee, K.H.; Massuti, B.; Hiret, S.; Yang, J.; et al. Tiragolumab plus Atezolizumab versus Placebo plus Atezolizumab as a First-Line Treatment for PD-L1-Selected Non-Small-Cell Lung Cancer (CITYSCAPE): Primary and Follow-up Analyses of a Randomised, Double-Blind, Phase 2 Study. Lancet. Oncol. 2022, 23, 781–792.
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      Kuzevanova, A.; Apanovich, N.; Mansorunov, D.; Korotaeva, A.; Karpukhin, A. Immune Checkpoint Receptors. Encyclopedia. Available online: https://encyclopedia.pub/entry/27013 (accessed on 07 February 2023).
      Kuzevanova A, Apanovich N, Mansorunov D, Korotaeva A, Karpukhin A. Immune Checkpoint Receptors. Encyclopedia. Available at: https://encyclopedia.pub/entry/27013. Accessed February 07, 2023.
      Kuzevanova, Anna, Natalya Apanovich, Danzan Mansorunov, Alexandra Korotaeva, Alexander Karpukhin. "Immune Checkpoint Receptors," Encyclopedia, https://encyclopedia.pub/entry/27013 (accessed February 07, 2023).
      Kuzevanova, A., Apanovich, N., Mansorunov, D., Korotaeva, A., & Karpukhin, A. (2022, September 08). Immune Checkpoint Receptors. In Encyclopedia. https://encyclopedia.pub/entry/27013
      Kuzevanova, Anna, et al. ''Immune Checkpoint Receptors.'' Encyclopedia. Web. 08 September, 2022.
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