Targeting the PD-1H (VISTA) Pathway to Overcome Immunosuppression in Acute Myeloid Leukemia - SUMMARY Acute Myeloid Leukemia (AML), driven by rapid myeloid cell proliferation, presents a significant challenge due to its high mortality and limited treatment options. Despite advances in AML biology, chemotherapy remains the primary treatment, often failing to prevent relapse. Immune checkpoint blockade (ICB) therapies, effective in solid tumors, show limited efficacy in AML, likely due to distinct immune pathways in its tumor microenvironment (TME). This underscores the need for therapies targeting AML’s unique immunosuppressive environment. PD- 1H (Programmed Death-1 Homolog, also known as VISTA) has emerged as a promising immunotherapeutic target. Our recent studies reveal that PD-1H is highly expressed in the AML microenvironment, and mouse models show that PD-1H promotes immune suppression and accelerates AML progression, underscoring its therapeutic potential. These findings set the stage for determining the mechanisms by which PD-1H regulates immune suppression in AML and its potential as a therapeutic target. Aim 1 seeks to elucidate the cellular and molecular mechanisms by which PD-1H mediates immune suppression in AML. We hypothesize that (1) PD-1H shifts myeloid cell populations from pro-inflammatory to anti-inflammatory states, and (2) uses its unique structural domains to interact with LRIG1 on T cells, leading to direct T cell suppression. To test this, we will use myeloid lineage-specific PD-1H knockout mice, combined with single-cell profiling and functional assays, to analyze how PD-1H regulates different myeloid lineages within the AML microenvironment. We will then use PD-1H structural mutants to identify critical functional domains underlying immune suppression. To examine LRIG1’s role as a receptor, we will employ LRIG1 knockout T cells and T cell-specific LRIG1 knockout mice to determine its role in T cell inhibition and AML progression. Aim 2 focuses on developing novel immunotherapeutic strategies by targeting the PD-1H pathway in AML. We hypothesize that PD-1H inhibition will enhance anti-AML immunity. To thoroughly assess the role of PD-1H in human AML, we will analyze longitudinal bone marrow samples from AML patients at various stages to track the expression dynamics of PD-1H and other immune checkpoint markers. We will test new monoclonal antibodies that fully block PD-1H/LRIG1 interaction, evaluating their efficacy in primary mouse AML models and humanized AML models with patient-derived xenografts. We will also test a novel combination of anti-PD-1H with anti-TIM3 in AML. This approach integrates patient-derived data with in vivo efficacy testing to support the translational potential of PD-1H-targeted therapies, laying the groundwork for clinical applications. This project combines mechanistic studies with innovative therapeutic approaches, aiming to establish PD- 1H as a central target in AML. By addressing AML's immune-suppressive TME through PD-1H, we hope to advance immunotherapeutic strategies that could significantly improve patient outcomes.
