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

Jing Pan,Ronald A Lubet,Charles R Myers,Weiguo Cui,Yian Wang,Gang Xin,Katie Palen,Chuanjia Yang,Bryon D Johnson,Li Wang,Yao Chen,Shizuko Sei,Qi Zhang,Robert H Shoemaker,Ming You,Achia Khatun

doi:10.1038/s42003-021-02381-x

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.

Highlights

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
A recent study using in vitro binding assays showed that there is no direct binding between CA170 and PD-L1, indicating that CA170 acts mainly via blocking VISTA immune checkpoint pathway[6]
We tested whether a combination of KRAS vaccine plus CA170 could synergize to prevent lung tumorigenesis in the Vinyl carbamate (VC)-induced primary lung tumor model

Summary

Introduction

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. During T cell activation, inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death protein 1 (PD-1), Lymphocyte-activation gene 3 (Lag-3), T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and V-domain Ig suppressor of T cell activation (VISTA) are induced to limit overstimulation of the immune system after antigen exposure[1] The ligands for these inhibitory receptors are upregulated in many types of cancer cells, antigen-presenting cells (APCs), and other immune cells, and the binding of these ligands to their receptors usually results in reduced T cell proliferation and activation. A combination of antigen-specific immunotherapy, such as peptide vaccination and immune checkpoint blockade should enhance both primary and secondary signaling events to increase antigenspecific T cell activation. The effects of CA170 on immunity in the tumor microenvironment were investigated using single-cell RNA-sequencing (scRNA-seq)

Methods

Results

Conclusion