The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead

Abstract

Immune checkpoints (ICs) have pivotal roles in regulating immune responses. The inhibitory ICs in the tumor microenvironment (TME) have been implicated in the immune evasion of tumoral cells. Therefore, identifying and targeting these inhibitory ICs might be critical for eliminating tumoral cells. V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory IC that is expressed on myeloid cells, lymphoid cells, and tumoral cells; therefore, VISTA can substantially regulate innate and adaptive anti-tumoral immune responses. Besides, growing evidence indicates that VISTA blockade can enhance the sensitivity of tumoral cells to conventional IC-based immunotherapy, e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. In this regard, the current study aimed to review the current evidence about the structure and expression pattern of VISTA, its role in TME, the clinicopathological significance of VISTA, and its prognostic values in various cancers. Besides, this review intended to collect the lessons from the recent pre-clinical and clinical studies and propose a strategy to overcome tumor immune-resistance states.

Keywords: VISTA; cancer; immune checkpoints; immune-resistance; immunotherapy.

Figure 1

Blocking the interaction between VISTA and VISTA-R can lead to T cell activation and the upregulation of IFN-γ, IL-2, IL-17, CXCL-11, CCL-3, and CCL-5. VISTA, V-domain Ig suppressor of T cell activation; VISTA-R, VISTA-receptor.

Figure 2

The upregulation of VISTA in prostate cancer after anti-CTLA-4 therapy. (A) The expression of CTLA-4 on immune cells, e.g., T cells and macrophages, and its interaction with tumoral cells can attenuate anti-tumoral immune responses. (B) The administration of anti-CTLA-4 can stimulate anti-tumoral immune responses. (C) After anti-CTLA-4 therapy, the upregulation of VISTA inhibits immune cell activation and leads to tumor expansion. (D) Dual VISTA/CTLA-4 blockade can elicit synergistic responses and leads to the elimination of prostate cancer cells. CTLA-4, cytotoxic T-lymphocyte-associated protein-4; VISTA, V-domain Ig suppressor of T cell activation.

Figure 3

CA-170, an orally administered agent, can directly block the interaction of PD-1/PD-L1 and VISTA/VISTA-receptor and reactivate T cells (85). VISTA, V-domain Ig suppressor of T cell activation, PD-1, Programmed cell death protein-1; PD-L1, Programmed death-ligand 1.