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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：
10365623
负责人：
RAYMOND B BIRGE
金额：
$ 50.82万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365623
关键词：
AREG gene Address Advanced Malignant Neoplasm Antigens Apoptotic Archives Autoimmunity Binding 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 Lead Ligands Light Lipids Malignant Neoplasms Mammary Neoplasms Mediating Modality Modeling Monoclonal Antibodies Mus Myelogenous Neoplasm Metastasis Organism Outcome PTGS2 gene Pathway interactions Patients Phosphatidylserines Physiological Protein S 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 macrophage 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.

项目概要： Tyro 3、Axl和Mertk（缩写为TAM受体）是同源I型受体家族，酪氨酸激酶（RTK）在生理条件下具有稳态功能，抑制炎症并维持多细胞生物体的组织耐受性。的配体 TAM是两种维生素K修饰的蛋白质，生长停滞特异性因子6（Gas 6）和蛋白S 结合凋亡细胞上的磷脂酰丝氨酸（PS），并在此过程中起桥接作用分子以促进凋亡细胞的清除（细胞凋亡）。虽然PS介导巨噬细胞增多症，最典型的是通过巨噬细胞上表达的Mertk，具有重要的体内平衡功能，以防止慢性炎症和自身免疫，发生在实体癌的肿瘤微环境（TME）中的外部化PS，随着Mertk在浸润性巨噬细胞上的表达，病理生理学上破坏PS- 介导的致耐受性功能以抑制宿主抗肿瘤免疫应答。中央本申请中的假设是组成性失调调节PS外化在TME中观察到，与表达Mertk的细胞浸润相结合，巨噬细胞作为一种重要的免疫抑制轴，抑制宿主的抗肿瘤作用免疫力该轴可能在广泛的实体癌中被激活以进行免疫逃逸，而且如果被治疗剂有效地靶向，也可能代表癌症的脆弱性。在这应用，我们概述了机械实验，以确定如何外化PS失调在TME（目标#1），以及确定的机制，Mertk作为一种抑制受体，以抑制宿主的抗肿瘤免疫和耐受性（目的#2）。在aim中 #3，我们提出了一系列临床前治疗性小鼠研究，以测试第一- 类内抗Mertk中和mAb与抗PD 1 mAb联合，以及探索和使用人类模型验证Mertk作为抑制性受体的生物学。总体而言，我们研究旨在开辟新的途径来询问一种新型的检查点抑制网络，免疫肿瘤学