Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights

Abstract

Immune checkpoints limit the activation of the immune system and serve an important homeostatic function but can also restrict immune responses against tumors. Inhibition of specific immune checkpoint proteins such as the B7:CD28 family members programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has transformed the treatment of various cancers by promoting the anti-tumor activation of immune cells. In contrast to these effects, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) regulates the steady state of the resting immune system and promotes homeostasis by mechanisms distinct from PD-1 and CTLA-4. The effects of VISTA blockade have been shown to include a decrease in myeloid suppression coupled with proinflammatory changes by mechanisms that are separate and distinct from other immune checkpoint proteins; in some preclinical studies these immune effects appear synergistic. Given the potential benefits of VISTA blockade in the context of cancer therapy, the second Annual VISTA Symposium was convened virtually on September 23, 2022, to review new research from investigators and immuno-oncology experts. Discussions in the meeting extended the knowledge of VISTA biology and the effects of VISTA inhibition, particularly on cells of the myeloid lineage and resting T cells, as three candidate anti-VISTA antibodies are in, or nearing, clinical development.

Keywords: PD-1; VISTA; checkpoint inhibitors (ICIs); immune checkpoint; immuno-oncology (IO); immunotherapy; myeloid.

Figure 1

Potential effects of VISTA blockade in the tumor microenvironment discussed at the meeting. One role of VISTA is to serve as a checkpoint on naïve T cells, impeding the earliest stages of T-cell activation. Blockade of VISTA brings T cells out of quiescence, then acts to expand and transform activated and exhausted T cells into effector cells. Further effects of VISTA blockade in the TME include enhanced presentation of antigens on monocytes, decreased recruitment of MDSCs, increased release of T-cell activating factors, and increased maturation of NK cells. These effects are further bolstered by increased MHC expression on TAMs and the reduced expression of genes promoting T-cell quiescence. The functional relevance of VISTA expression on tumor cells has yet to be uncovered. APC, antigen-presenting cell; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; NK, natural killer; TAM, tumor-associated macrophage.