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Review
. 2023 Feb 20:14:1086102.
doi: 10.3389/fimmu.2023.1086102. eCollection 2023.

VISTA expression and patient selection for immune-based anticancer therapy

Alexander S Martin  1 , Michael Molloy  2 , Andrey Ugolkov  3 , Reinhard W von Roemeling  3 , Randolph J Noelle  2   4 , Lionel D Lewis  4 , Melissa Johnson  5 , Laszlo Radvanyi  6 , Robert E Martell  1   3
Affiliations
Review

VISTA expression and patient selection for immune-based anticancer therapy

Alexander S Martin et al. Front Immunol. .

Abstract

V-domain Ig suppressor of T-cell activation (VISTA) is a B7 family member that plays key roles in maintaining T cell quiescence and regulation of myeloid cell populations, which together establish it as a novel immunotherapy target for solid tumors. Here we review the growing literature on VISTA expression in relation to various malignancies to better understand the role of VISTA and its interactions with both tumor cells and immune cells expressing other checkpoint molecules within the tumor microenvironment (TME). The biology of VISTA creates several mechanisms to maintain the TME, including supporting the function of myeloid-derived suppressor cells, regulating natural killer cell activation, supporting the survival of regulatory T cells, limiting antigen presentation on antigen-presenting cells and maintaining T cells in a quiescent state. Understanding these mechanisms is an important foundation of rational patient selection for anti-VISTA therapy. We provide a general framework to describe distinct patterns of VISTA expression in correlation with other known predictive immunotherapy biomarkers (programmed cell death ligand 1 and tumor-infiltrating lymphocytes) across solid tumors to facilitate investigation of the most efficacious TMEs for VISTA-targeted treatment as a single agent and/or in combination with anti-programmed death 1/anti-cytotoxic T lymphocyte antigen-4 therapies.

Keywords: VISTA; biomarkers; cancer; cancer immunotherapy; immune checkpoint; tumor immunity; tumor microenvironment.

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Conflict of interest statement

AM reports research support from the NIH. MM has served on advisory boards and as a consultant for Curis, Inc. and for ImmuNext, and has intellectual property for VISTA antibodies. AU was employed by Curis, Inc. RR is employed by Curis, Inc. RN employed by ImmuNext, and has served on advisory boards and as a consultant for Curis, Inc, and reports research support from the NIH. LL has served on advisory boards and as a consultant for Curis, Inc. and has received research support from Curis, Inc; and reports additional research support from AbbVie, AstraZeneca, and Bristol Meyers Squibb, has served on a data safety monitoring board for G1 Therapeutics, and is the vice chair of the pharmacogenomics and population pharmacology committee of the Alliance for Clinical Trials in Oncology. MJ has received research support from Curis, Inc.; and reports additional research support to institution from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingeheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Cytomx, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicine, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics, Black Diamond, Carisma Therapeutics, Elicio Therapeutics, EQRx, Impact, Kartos Therapeutics, Mirati Therapeutics, Palleon Pharmaceuticals, and Rain Therapeutics, and has served as a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, and VBL Therapeutics. LR has served on advisory boards and as a consultant for Curis, Inc. RM is employed by Curis, Inc. This manuscript received medical writing support funded by Curis, Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The major NCRs in the Ig superfamily are shown at the junction between the CTL and interacting cell (e.g., tumor cell, APC, myeloid cell, etc.). VISTA serves dual immunosuppressive roles as both a ligand on myeloid cells/APCs with PSGL-1 being its receptor on CTLs and a receptor on CTLs with VSIG-3 as its ligand. Additionally, there is potential for VISTA–VISTA homotypic interaction. Blocking antibodies toward these targets is showing great promise in immunotherapy. APCs, antigen presenting cell; CTL, cytotoxic T lymphocyte; Gal-3, galectin-3; Gal-9, galectin-9; LAG-3, lymphocyte activation gene 3; LSECtin, liver and lymph node sinusoidal endothelial cell C-type lectin; MHC I, major histocompatibility complex class I; MHC II, major histocompatibility complex class II; NCR, negative checkpoint receptors; PSGL-1, P-selectin glycoprotein ligand 1; TCR, T cell receptor; TIGIT, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM-3: T cell immunoglobulin mucin-3; TME, tumor microenvironment; VSIG-3, V-set and Ig domain-containing 3.
Figure 2
Figure 2
VISTA expression in normal tissues/cells. Y axis: Consensus normalized expression in transcripts per million (TPM) for 55 tissue types, created by combining the data from the three transcriptomics datasets. Color coding is based on tissue groupings with common functional features. HPA, Human Protein Atlas; GTEx, Genotype-Tissue Expression project and FANTOM5.
Figure 3
Figure 3
Types of tumor microenvironment targets for potential anti-cancer immunotherapies. Cancers are categorized into 4 different tumor microenvironments based on the presence or absence of CD8+ TILs and PD-L1 expression. We describe the potential impact of VISTA expression to each of these TME categories to facilitate investigation of anti-VISTA agents to improve upon immunotherapeutic strategies for each of these TME types. CD, Cluster of Differentiation; MDSC, myeloid derived suppressor cell; MHC I, major histocompatibility complex class I; PD-L1, programmed cell death ligand 1; PD-1, programmed cell death protein 1; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; VISTA, V-domain Ig suppressor of T-cell activation.
Figure 4
Figure 4
Potential mechanisms and impacts of VISTA antagonism. VISTA plays multiple roles in controlling immune responses. VISTA antagonism 1) induces a shift in MDSC function, reduces MDSC suppressive activity and enhances the potential for improved antitumor effect through macrophage activation, 2) lowers the threshold of activation for quiescent T cells and allows a greater percentage of T cells to respond to neo-antigens, 3) activates NK cells that may result in independent anticancer effects via antibody-directed cellular cytotoxicity, 4) enhances APC maturation to effectively present antigens to induce a T-cell response, and 5) expands and transforms activated and exhausted T cells into effector cells. APC, antigen presenting cell; CCR2, C-C motif chemokine receptor; CD, cluster of differentiation; CXCR2, CXC motif chemokine receptor 2; MDSC, myeloid-derived suppressor cell; MΦ, macrophage; NK, natural killer cell.
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