Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

Abstract

Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8⁺ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4⁺ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.

Pan, Chen, Zhang et al. investigated the anti-cancer efficacy of CA170, a small molecule agonist of VISTA, on mouse lung tumorigenesis. When combined with a MHCII-directed KRAS peptide vaccine, the authors reported that CA170 suppressed lung tumor development by increasing CD8⁺ T cell and decreasing MDSC and Treg infiltration, while the Kras vaccine induced CD4⁺ effector T cell expansion