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.

项目摘要： TYRO3，AXL和MERTK（缩写的TAM受体）是I型受体的家族在生理条件下具有稳态功能的酪氨酸激酶（RTK）炎症并保持多细胞生物的组织耐受性。配体 TAM是两个维生素K-修饰蛋白，生长阻止特异性因子6（GAS6）和蛋白质S （proS1）结合凋亡细胞上磷脂酰丝氨酸（PS）的结合，在这样做时，它充当桥接分子以促进凋亡细胞的清除率（肿瘤性吞噬作用）。同时PS介导的通过在巨噬细胞上表达的MERTK在最具标志性上的胚细胞增多症具有重要稳态功能可防止慢性炎症和自身免疫性固体癌的肿瘤微环境（TME）中发生的外部化PS，结合随着MERTK在浸润巨噬细胞上的表达，病态生理学颠覆了PS- 介导的耐受性功能以抑制宿主抗肿瘤免疫反应。中央该应用中的假设是组成性调节的PS外部化在TME中观察到，结合表达MERTK的渗透巨噬细胞，充当重要的免疫抑制轴以抑制宿主抗肿瘤免疫。该轴可能会在各种固体癌中激活以进行免疫逃生，但如果有效地由治疗剂靶向，也可能代表癌症中的脆弱性。在这个应用，我们概述了机械实验以确定外部化PS的失调方式在TME（AIM＃1）中，并确定MERTK充当抑制性的机制巨噬细胞上的受体抑制宿主的抗肿瘤免疫和耐受性（AIM＃2）。目标＃3，我们提出了一系列临床前治疗小鼠研究，以测试第一次的组合在阶层抗MERTK中和MAB与抗PD1 MAB结合使用，以及探索和探索和使用人类模型验证MERTK作为抑制受体的生物学。总体而言，我们的研究旨在打开新的途径，以询问一种新型的检查点抑制网络在免疫肿瘤学中。