VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy

Abstract

In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment. More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors. Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival. Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.

Figure 1

Negative checkpoint regulators in the TME. The major NCRs in the Ig superfamily are shown in CTL and interacting cell type (e.g., tumor cell, myeloid cell, etc.). Blocking antibodies toward these targets is showing great promise in immunotherapy.

Figure 2

Understanding TME composition for personalized combination of immunotherapeutic agents. Left, expression of VISTA, CD8, and CD11b was codetected in formalin-fixed paraffin-embedded tissue sections of colon and lung cancer tumor lesions. In these merged image panels, colocalization of VISTA (green) and CD11b (magenta) signal appears white. Right, tailored approach for tumor expressing PDL1 and VISTA in different cellular compartments of the TME. VISTA and PDL1 interfere with different subsets of CTL and distinctly affect their activities. Synergistic effects of dual VISTA and PDL1 blockade would be expected to enhance CTL and activities and boost antitumoral immunity.