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:
  • 金额:
    $ 50.82万
  • 依托单位:
  • 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

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

项目成果

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RAYMOND B BIRGE其他文献

RAYMOND B BIRGE的其他文献

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{{ truncateString('RAYMOND B BIRGE', 18)}}的其他基金

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
  • 批准号:
    10554443
  • 财政年份:
    2022
  • 资助金额:
    $ 50.82万
  • 项目类别:
Non-canonical signal pathway for Crk in breast cancer
乳腺癌中 Crk 的非经典信号通路
  • 批准号:
    8701004
  • 财政年份:
    2012
  • 资助金额:
    $ 50.82万
  • 项目类别:
Non-canonical signal pathway for Crk in breast cancer
乳腺癌中 Crk 的非经典信号通路
  • 批准号:
    8402232
  • 财政年份:
    2012
  • 资助金额:
    $ 50.82万
  • 项目类别:
Non-canonical signal pathway for Crk in breast cancer
乳腺癌中 Crk 的非经典信号通路
  • 批准号:
    9246662
  • 财政年份:
    2012
  • 资助金额:
    $ 50.82万
  • 项目类别:
Non-canonical signal pathway for Crk in breast cancer
乳腺癌中 Crk 的非经典信号通路
  • 批准号:
    8509636
  • 财政年份:
    2012
  • 资助金额:
    $ 50.82万
  • 项目类别:
Targeting FKBP52 and Copper in Alzheimer's Disease
靶向 FKBP52 和铜治疗阿尔茨海默病
  • 批准号:
    7150136
  • 财政年份:
    2006
  • 资助金额:
    $ 50.82万
  • 项目类别:
Targeting FKBP52 and Copper in Alzheimer's Disease
靶向 FKBP52 和铜治疗阿尔茨海默病
  • 批准号:
    7270115
  • 财政年份:
    2006
  • 资助金额:
    $ 50.82万
  • 项目类别:
IDENTIFICATION OF A NOVEL SIGNAL PATHWAY FOR NGF
NGF 新型信号通路的鉴定
  • 批准号:
    6342942
  • 财政年份:
    1999
  • 资助金额:
    $ 50.82万
  • 项目类别:
IDENTIFICATION OF A NOVEL SIGNAL PATHWAY FOR NGF
NGF 新型信号通路的鉴定
  • 批准号:
    6331057
  • 财政年份:
    1999
  • 资助金额:
    $ 50.82万
  • 项目类别:
IDENTIFICATION OF A NOVEL SIGNAL PATHWAY FOR NGF
NGF 新型信号通路的鉴定
  • 批准号:
    2758467
  • 财政年份:
    1999
  • 资助金额:
    $ 50.82万
  • 项目类别:

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