Understanding how the interaction between Lag3 deficiency and hypercholesterolemia impact anti-tumor immunity and cardiovascular disease in a melanoma model

点击翻译按钮获取中文摘要

Project Summary Immune checkpoint inhibitors (ICIs) elicit anti-tumor immunity by blocking various regulatory axes that normally dampen the capacity of T lymphocytes to target tumor cells. While ICI therapies have revolutionized the field of oncology by providing treatment options for otherwise intractable tumors, only a subset of patients experience meaningful clinical benefits, while adverse inflammatory and autoimmune toxicities often occur. To improve treatment outcomes, efforts have been underway to establish biomarkers that can predict both therapeutic, as well as adverse responsiveness to particular ICIs. The most recently FDA-approved ICI is a monoclonal antibody that targets Lymphocyte Activation Gene-3 (anti-LAG3, relatlimab), which is expressed on many immune cell types. Knowledge of LAG3's mechanism of action is mainly limited to its intrinsic role in regulating the function of T cells. Thus, understanding the intrinsic role of LAG3 in other immune cells that are critical for programming anti- tumor immunity as well as pathologic inflammation should provide important insights into how anti- LAG3 elicits both beneficial therapeutic, and adverse patient responses. This project seeks to fill this critical knowledge gap based on our two key preliminary findings. First, Lag3 plays an intrinsic role in murine antigen presenting dendritic cells (DCs) to limit their activation and capacity to prime naive T cells to proliferate and develop effector functionality. Second, human patients with plasma LAG3 deficiency have decreased levels of circulating IL-10, and increased risk for cardiovascular disease. This forms the basis of our central hypothesis that Lag3-deficient DCs have an enhanced capacity to prime tumor-specific effector T cells, leading to reduced tumor growth, but also adverse vascular inflammation. This will be tested using two novel and complimentary genome-edited mouse models of DC-conditional Lag3 expression. Specifically, Aim 1 will determine the DC-intrinsic role of Lag3 in priming effector T cells and anti-tumor immunity in a melanoma model, while Aim 2 will analyze how the interaction between hypercholesterolemia and Lag3 deficiency impacts both ICI cancer therapy efficacy as well as induced adverse cardiovascular inflammation. In accomplishing these aims, we will add a new dimension to our mechanistic understanding of the clinically relevant immunotherapeutic target Lag3, identify potential biomarkers to predict responsiveness to anti-LAG3 therapy, and establish an experimental framework for future studies to develop strategies to minimize adverse cardiovascular pathology caused by blocking LAG3, while maintaining anti-tumor immunity.