Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

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Oncology meets immunology: the cancer-immunity cycle.

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Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

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Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

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Enhancement of Antitumor Immunity by CTLA-4 Blockade

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Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

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The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

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Nivolumab and ipilimumab versus ipilimumab in untreated melanoma

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CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition

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PD-L1 expression as a predictive biomarker in cancer immunotherapy

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PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity

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Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma

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CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

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Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4

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CTLA-4 can function as a negative regulator of T cell activation

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Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation

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Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

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The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity

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CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer

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CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms

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PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors

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Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

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Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell Responses

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T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

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CTLA-4 is a second receptor for the B cell activation antigen B7.

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Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

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TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion

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Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

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The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

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Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma

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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

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Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

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Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

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First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial

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Role of LAG-3 in Regulatory T Cells

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Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients

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Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma

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The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8 + T Cell Effector Function

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FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT

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CTLA-4–Ig regulates tryptophan catabolism in vivo

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Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

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TOX is a critical regulator of tumour-specific T cell differentiation

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Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways

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CD8+ T cell differentiation and dysfunction in cancer

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PD-1 + regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer

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Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies

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TIM3 comes of age as an inhibitory receptor

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LAG-3, a novel lymphocyte activation gene closely related to CD4.

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Coinhibitory Pathways in Immunotherapy for Cancer

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Treg cells expressing the co-inhibitory molecule TIGIT selectively inhibit pro-inflammatory Th1 and Th17 cell responses

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Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3

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NR4A transcription factors limit CAR T cell function in solid tumours

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Tumor-infiltrating NY-ESO-1–specific CD8 ⁺ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer

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The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells

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TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 ⁺ T cell exhaustion

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CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

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VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses

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Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy

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Reversal of the TCR Stop Signal by CTLA-4

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VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer

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Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.

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Anti-TIM3 Antibody Promotes T Cell IFN-γ–Mediated Antitumor Immunity and Suppresses Established Tumors

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Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions

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Ipilimumab: An Anti-CTLA-4 Antibody for Metastatic Melanoma

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Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

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Revisiting the PD-1 pathway

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Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial

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Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

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Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells

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PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus

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Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8+ T cell in HCC patients

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A Disintegrin and Metalloprotease (ADAM) 10 and ADAM17 Are Major Sheddases of T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)

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T Cell Ig and Mucin Domain–Containing Protein 3 Is Recruited to the Immune Synapse, Disrupts Stable Synapse Formation, and Associates with Receptor Phosphatases

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Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types

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The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

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Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines

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Molecular Pathways and Mechanisms of LAG3 in Cancer Therapy

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VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

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Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation

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A single-cell atlas of diffuse large B cell lymphoma

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V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma

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Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

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Tim-3 promotes tumor-promoting M2 macrophage polarization by binding to STAT1 and suppressing the STAT1-miR-155 signaling axis

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PD-1 and LAG-3 Dominate Checkpoint Receptor–Mediated T-cell Inhibition in Renal Cell Carcinoma

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Regulation of expression of the human lymphocyte activation gene-3 ( LAG-3 ) molecule, a ligand for MHC class II

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Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment

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A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer

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Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

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Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma

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LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma

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Single-cell characterization of anti–LAG-3 and anti–PD-1 combination treatment in patients with melanoma

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MicroRNA Profile of Circulating CD4-positive Regulatory T Cells in Human Adults and Impact of Differentially Expressed MicroRNAs on Expression of Two Genes Essential to Their Function

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PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity

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Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis

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Regulation of Surface and Intracellular Expression of CTLA‐4 on Human Peripheral T Cells

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LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade

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TIGIT blockade repolarizes AML-associated TIGIT + M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis

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Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

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TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

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Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma

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Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors

Crosby, E. J., Wei, J.-P., Yang, X. Y., Lei, G., Wang, T., Liu, C.-X., Agarwal, P., Korman, A. J., Morse, M. A., Gouin, K. H., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1421891 · Cited by 84 · see citing works

Clinically approved combination immunotherapy: Current status, limitations, and future perspective

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Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).

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PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express targetable activating and inhibitory receptors

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Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade

Roussel, M., Le, K.-S., Granier, C., Gutierrez, F. L., Foucher, E. D., Gallou, S. L., Pangault, C., Xerri, L., Launay, V., Lamy, T., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020003080 · Cited by 69 · see citing works

Prognostic implication of TIM-3 in clear cell renal cell carcinoma

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Rationally targeted anti-VISTA antibody that blockades the C-C’ loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner

Thakkar, D., Paliwal, S., Dharmadhikari, B., Guan, S., Liu, L., Kar, S., Tulsian, N. K., Gruber, J. J., DiMascio, L. N., Paszkiewicz, K. H., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003382 · Cited by 67 · see citing works

Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations

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Immunoregulation of Dendritic Cells by the Receptor T cell Ig and Mucin Protein-3 via Bruton’s Tyrosine Kinase and c-Src

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Prognostic Value of T Cell Immunoglobulin Mucin-3 in Prostate Cancer

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VISTA: A Promising Target for Cancer Immunotherapy?

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Structural insight into T cell coinhibition by PD-1H (VISTA)

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ARC-7: Randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC).

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The Expression Pattern and Clinical Significance of the Immune Checkpoint Regulator VISTA in Human Breast Cancer

Xie, X., Zhang, J., Zhongyuan, S., Liu, W., Hu, X., Qie, C., Chen, W., Wang, Y., Wang, L. L., Jiang, J., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.563044 · Cited by 55 · see citing works

A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment

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TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation

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AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors

Frentzas, S., Kao, S., Gao, R., Zheng, H. W., Rizwan, A., Budha, N. R., Pedroza, L. D. L. H., Tan, W., & Meniawy, T. M. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005829 · Cited by 53 · see citing works

VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance

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New emerging targets in cancer immunotherapy: the role of VISTA

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Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma

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P3.04-15 IDO and Tim3 Gene Expression is Correlated in NSCLC Patients with Low PDL1 Gene Expression

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SY03-4 TIGIT blockade therapy from basic insights to clinics

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TIGIT and CD 96: new checkpoint receptor targets for cancer immunotherapy

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γδ T cells as unconventional targets of checkpoint blockade

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Immune checkpoint expression on peripheral lymphocytes in cervical cancer patients: moving beyond the PD-1/PD-L1 axisPreprint

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