Investigating the Role of VISTA in Driving Immune Evasion in Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) has a high mortality rate following standard therapies. Blockade of immune checkpoint receptors (ICRs) has revolutionized therapy for solid tumors, yet it has not significantly improved survival in AML patients. This unmet clinical need calls for the identification and targeting of alternative ICRs. VISTA, a next-generation ICR, is a promising target for cancer therapy; however, its role in modulating antileukemia immunity remains unclear and there are significant knowledge gaps in understanding the signaling mechanisms of VISTA. Our preliminary studies suggest that VISTA intrinsically promotes the differentiation of immunosuppressive myeloid cells (MDSCs). This proposal aims to test the hypothesis that blocking VISTA- mediated signaling in myeloid cells will reduce MDSC differentiation and improve the immunogenicity of leukemic cells, thereby leading to effective antileukemia immunity. To address this hypothesis, we will first investigate the signaling mechanisms of VISTA in myeloid cells (Specific Aim 1). Next, we will evaluate the therapeutic potential of VISTA-specific inhibitors in multiple preclinical models of AML (Specific Aim 2). The successful completion of these studies will establish VISTA as a critical ICR in AML and warrant the targeting of VISTA for treating AML.