Abstract 1618: Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA

Abstract Immunotherapy using monoclonal antibodies to block immune checkpoints is becoming a mainstream therapy for multiple late-stage cancers owing to their efficacy in improving clinical outcomes. However, relatively low response rates and persistent clinical side effects indicate the need for additional strategies to block immune-suppressive pathways. VISTA (V-domain Ig Suppressor of T cell Activation), which is expressed on cells of the myeloid and lymphoid lineages, is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. We found that CA170, a novel orally bioavailable tripeptide small molecule antagonist of VISTA and PD-L1/PD-L2, has potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHC-II-directed KRAS peptide vaccine. Flow cytometry and single cell RNA sequencing (scRNA-seq) revealed that CA170 increases CD8+ T cell infiltration and effector functions by decreasing the tumor infiltration of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), while the KRAS vaccine primarily induces expansion of CD4+ effector T cells. Inhibition of VISTA by CA170 has strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and promotes an adaptive T cell tumor-specific immune response that enhances efficacy of the KRAS vaccine. Citation Format: Jing Pan, Yao Chen, Qi Zhang, Achia Khatun, Katie Palen, Li Wang, Chuanjia Yang, Bryon D. Johnson, Charles R. Myers, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Weiguo Cui, Ming You. Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1618.