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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.

项目总结： Tyro3、Ax1和MerTK(缩写为受体)是一个同源的I型受体家族在生理条件下具有动态平衡功能的酪氨酸激酶(RTK) 在多细胞生物体中抑制炎症和维持组织耐受性。的配基 TAMs是两种维生素K修饰的蛋白质，生长停滞特异性因子6(Gas6)和蛋白质S (Pros1)与凋亡细胞上的磷脂酰丝氨酸(PS)结合，并在此过程中起到桥接的作用有助于清除凋亡细胞的分子(胞泡吞噬)。而PS介导的巨噬细胞上表达的MerTK最具代表性的吞噬作用具有重要的作用体内平衡功能，以防止慢性炎症和自身免疫，构成出现在实体癌肿瘤微环境(TME)中的外部性PS 通过MerTK在浸润性巨噬细胞上的表达，病理生理上颠覆PS- 介导的致耐受功能抑制宿主抗肿瘤免疫反应。中环这个应用中的假设是，结构性的dys调节的PS外化在TME中观察到，结合MerTK表达的渗透巨噬细胞是抑制宿主抗肿瘤的重要免疫抑制轴豁免权。这个轴很可能在广泛的实体癌症中被激活，以进行免疫逃避，但如果有效地被治疗学靶向，也可能代表癌症的脆弱性。在这应用，我们概述了机制实验，以确定外部化的PS是如何失调的在TME中(目标1)，以及确定MerTK作为抑制物的机制巨噬细胞上的受体抑制宿主抗肿瘤免疫和耐受性(目标2)。在AIM #3，我们提出了一系列临床前治疗性小鼠研究，以测试第一个- 类内抗MerTK中和单抗与抗PD1单抗的结合，以及探索和利用人体模型验证MerTK作为抑制性受体的生物学特性。总的来说，我们的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在免疫肿瘤学方面。