VISTA: A Promising Target for Cancer Immunotherapy?

Abstract

Agents targeting the B7 family co-inhibitory receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1), or its ligand (PD-L1), have a pivotal role in clinical practice. V-domain Ig suppressor of T-cell activation (VISTA) is a protein highly conserved between species, with a similar amino acid sequence to the B7 family members, characterized by a particularly structural homology to PD-1. It has been counted as an emerging target within the list of novel targetable immune checkpoints in oncology. Physiologically, VISTA exerts a regulatory function on the immune system at several levels, particularly by modulating T cells activation. Its altered activity plays a role in many autoimmune diseases, and its expression has been found to be prognostically implicated in different cancer types in preclinical models. We hereby present the main evidence on the value of VISTA as an immune checkpoint in solid and hematological malignancies. We also review its value as a potential target for cancer immunotherapy, by reporting the results of Phase I and II clinical trials assessing the use of drugs targeting VISTA. The complexity of its pathway, along with some unclear biological aspects concerning its molecular interactions, currently represent a limit to the applicability of VISTA as an effective biomarker for immunotherapy in oncology. A deeper characterization of this immune checkpoint may help defining its value within immune signatures of solid and hematological malignancies, and to design future therapeutic strategies.

VISTA Is a Diagnostic Biomarker and Immunotherapy Target of Aggressive Feline Mammary Carcinoma Subtypes

“…The statistical analysis of the immunostaining in the FFPE FMC samples revealed a higher expression of VISTA in cancer cells when compared to TILs ( p < 0.0001), contrary to what is reported in a variety of human cancers [ 29 , 32 , 43 , 44 , 63 , 64 ]. Interestingly, a positive correlation was obtained by the increase in VISTA expression in cancer cells and TILs ( p = 0.0022), which suggests a paracrine mechanism used by cancer cells to communicate with the immune system, as reported for PD-L1 in breast cancer patients [ 65 , 66 , 67 ].…”

“…In these samples, a homogenous VISTA expression was observed in TILs, while in cancer cells a heterogeneous VISTA expression was obtained, according to the findings in human cancers. Thus, this result indicates different cancer cell subpopulations that vary in their genetic, phenotypic, or behavioral characteristics, being associated with cancer progression and therapeutic resistance [ 62 , 63 ].…”

Immune Regulatory Processes of the Tumor Microenvironment under Malignant Conditions

“…Observations in malignant settings suggest that VISTA expression suppresses the T cell-mediated response and promotes immune evasion [79][80][81][82]. Additionally, it was reported that VISTA is mainly expressed on immune cells, especially CD8+ T cells, and is associated with immunosuppressive conditions in various tumor types, including melanoma, acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), small-lung-cell carcinoma, gastric cancer, and colorectal cancer, as reviewed in detail by ElTanbouly et al [83] and Tagliamento et al [84].…”

Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy

“…Particularly, inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death receptor (PD-1) and PD-ligand 1 (PD-L1) checkpoints, which regulate priming and effector phases of T-cell activation, respectively, were approved by the FDA ( Table 3 ) [ 182 ]. Clinical trials using other immune checkpoint inhibitors are ongoing, targeting T cell immunoglobulin and mucin-containing protein 3 (TIM-3) (NCT03311412, NCT02817633, NCT03307785) [ 183 , 184 ], lymphocyte activation gene-3 (LAG-3) (NCT03311412, NCT03538028, NCT03156114) [ 184 , 185 , 186 ], V-domain lg suppressor of T cell activation (VISTA) (NCT02671955, CTRI/2017/12/01 1026) [ 187 , 188 ], human endogenous retrovirus-h long terminal repeat-associating protein 2 (HHLA2), and T cell lg and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) (NCT04746924, NCT04866017) [ 189 ]. Most of the ICIs proved a limited benefit with 10%–20% overall response rates of monotherapy [ 190 ].…”