Immunoregulatory functions of VISTA

Abstract

Utilization of negative checkpoint regulators (NCRs) for cancer immunotherapy has garnered significant interest with the completion of clinical trials demonstrating efficacy. While the results of monotherapy treatments are compelling, there is increasing emphasis on combination treatments in an effort to increase response rates to treatment. One of the most recently discovered NCRs is VISTA (V-domain Ig-containing Suppressor of T cell Activation). In this review, we describe the functions of this molecule in the context of cancer immunotherapy. We also discuss factors that may influence the use of anti-VISTA antibody in combination therapy and how genomic analysis may assist in providing indications for treatment.

Keywords: VISTA; PD-1H; cancer; immunotherapies.

Figure 1. VISTA function as a ligand and a receptor

Potential interactions that may occur are shown and how targeting with a blocking anti-VISTA antibody can affect these results.

Figure 2. Mechanisms of immunotherapy

Anti-tumor T cell responses can be modulated by targeting different cell types and arms of immunity. 1 | Immunological Cell Death: tumor cell death induced by radiotherapy or some chemotherapies provide antigen and/or released adjuvant factors that elicit tumor-specific immunity. These treatments may also increase the diversity of the TCR repertoire. 2 | Vaccines: peptides, proteins and allogeneic or autologous tumor cell vaccines may also be used to elicit tumor-specific responses. Some vaccines use cells modified to provide additional adjuvant activity. For example, Gvax, consists of tumor cells modified to release GM-CSF to enhance antigen presentation. 3| Enhanced Innate Immunity: Myeloid cells within tumors may contribute to creating an immunosuppressed environment. Treatments may modulate myeloid activity toward a more inflammatory type sustaining adaptive immune responses 4 | Treg Modulation. Some treatments can either interfere with Treg activity or alter the T effector to Treg balance. 5 | Effector T cell mobilization. Immunotherapies may increase the infiltration of tumors with T cells 6 | Release from Exhaustion. Blockade of negative checkpoints may allow reinvigoration of exhausted cells and restore proliferation and effector function. PD-1 - PD-L1 is the principal pathway, but other negative checkpoints such as LAG-3, TIGIT and TIM-3 contribute to dysfunction of exhausted cells.

Figure 3. Association between VISTA expression and myeloid infiltration across tumor types

A. Boxplots comparing the distribution of VISTA expression across 9 different TCGA tumor types. Each box spans quartiles with bold lines representing the median VISTA expression level in each tumor type. All outliers were excluded in the plot. B. Spearman correlations between VISTA expression and infiltration levels of different myeloid cell types. Myeloid cell infiltration was inferred using patient gene expression data (87).