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Targeting a phosphatidylserine/TAM receptor/PD-L1 axis as a vulnerability in cancer

靶向磷脂酰丝氨酸/TAM 受体/PD-L1 轴作为癌症的脆弱性

基本信息

批准号：
10554443
负责人：
RAYMOND B BIRGE
金额：
$ 47.36万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554443
关键词：
AREG gene Abbreviations Address Advanced Malignant Neoplasm Antigens Apoptotic Archives Autoimmunity Binding Proteins Biology Breast Cancer Model Cancerous Caspase Cells Chronic Clinical Clinical Trials Cross Presentation FDA approved Family Future Gene Expression Genes Growth Human Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immunooncology Infiltration Inflammation Investigation Ligands Lipids Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Modality Modeling Monoclonal Antibodies Mus Myelogenous Neoplasm Metastasis Organism Outcome PTGS2 gene Pathway interactions Patients Phosphatidylserines Physiological Proteins Receptor Protein-Tyrosine Kinases Resolution Role Series Signal Transduction Solid Testing Therapeutic Tissues Tumor Escape Tumor Immunity Tumorigenicity Validation Vitamin K anti-CTLA4 anti-PD-1 anti-PD-L1 anti-tumor immune response cancer type experimental study human model immune checkpoint immune checkpoint blockade immunogenicity in vivo ipilimumab malignant breast neoplasm mouse model neutralizing monoclonal antibodies novel phosphatidylserine receptor pre-clinical prevent programmed cell death ligand 1 receptor targeted treatment triple-negative invasive breast carcinoma tumor microenvironment tumor progression

项目摘要

Project Summary: Tyro3, Axl, and Mertk (abbreviated TAM receptors) are a family of homologous type I Receptor Tyrosine Kinases (RTKs) that have homeostatic functions under physiological conditions to dampen inflammation and maintain tissue tolerance in multi-cellular organisms. The ligands for TAMs are two vitamin K- modified proteins, Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) that bind phosphatidylserine (PS) on apoptotic cells, and in doing so, act as bridging molecules to facilitate the clearance of apoptotic cells (efferocytosis). While PS-mediated efferocytosis, most emblematically via Mertk expressed on macrophages, have important homeostatic functions to prevent chronic inflammation and autoimmunity, the constitutively externalized PS that occurs in the tumor microenvironment (TME) of solid cancers, in combination with the expression of Mertk on infiltrating macrophages, patho-physiologically subvert PS- mediated tolerogenic functions to suppress host anti- tumor immune responses. The central hypothesis in this application is that constitutively dys- regulated PS externalization observed in the TME, in combination with the infiltration of Mertk-expressing macrophages, act as an important immune inhibitory axis to suppress host anti- tumor immunity. This axis is likely to be activated in a wide range of solid cancers for immune escape, but also may represent vulnerability in cancer if effectively targeted by therapeutics. In this application, we outline mechanistic experiments to identify how externalized PS is dysregulated in the TME (aim #1) as well as determine the mechanisms by which Mertk acts as an inhibitory receptor on macrophages to suppress host anti-tumor immunity and tolerance (aim #2). In aim #3, we propose a series of pre-clinical therapeutic mouse studies to test combinations of a first- in-class anti-Mertk neutralizing mAb in combination with anti-PD1 mAb, as well as explore and validate the biology of Mertk as an inhibitory receptor using human models. Collectively, our studies aim to open up new avenues to interrogate a novel type of checkpoint inhibitory network in immuno-oncology.

项目总结: