Effects of Complement on the Tumor Microenvironment in Lung Cancer

补体对肺癌肿瘤微环境的影响

基本信息

  • 批准号:
    10303019
  • 负责人:
  • 金额:
    $ 39.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-11 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Lung cancer is the leading cause of cancer death in both men and women, and overall survival has not significantly improved over the last 25 years for the majority of patients. Evasion from immune attack is a hallmark of cancer and is mediated by interactions between cancer cells and the tumor microenvironment (TME). Established tumors, including lung cancer, adopt a variety of strategies to block immune attack, and targeting these pathways has shown promise as a therapeutic approach. While less studied, it is also likely that immunoevasion is critical for tumor initiation. The complement system is a component of the innate immune system, which interfaces with the adaptive immune system. Complement activation occurs through three major pathways: the classical, the alternative and the lectin pathway. All of these trigger a series of proteolytic cascades that converge in the covalent fixation of C3b to the surface of target cells. Deposited C3b leads to formation of the C5 convertase, which cleaves C5 to produce C5a and ultimately the formation of C5b- 9, designated the membrane attack complex (MAC), which can cause lysis of target cells. C3a and C5a (anaphylatoxins), byproducts of complement activation, are inflammatory mediators that bind to receptors on multiple cells of the TME. Initially it was proposed that activation of complement initiated by antibody binding to cancer cells would inhibit cancer by MAC-dependent killing of cancer cells. However, recent studies by our group and others have shown that anaphylatoxins (C3a/C5a), promote cancer progression by acting on the TME to engage immunoevasive pathways. Using a novel orthotopic immunocompetent model of non-small cell lung cancer (NSCLC), we have shown that complement is activated in lung tumors, and inhibiting complement either genetically or pharmacologically blocks tumor progression. However, how complement is activated and how it regulates tumor progression are not well understood. This project will answer these questions using relevant models of lung cancer initiation and progression with distinct oncogenic drivers. The central premise of this application is that activation of complement directly contributes to lung cancer initiation and progression through direct effects on innate immune cells leading to immunosuppression. The MPI project is a collaboration between investigators with experience in the biology of lung cancer (Nemenoff) and complement biology (Thurman). We will employ an innovative panel of genetic mouse models, as well as novel methodologies to assess the role of complement in altering the TME. Three specific aims are proposed. Aim 1 will identify mechanisms of complement activation in established lung tumors. Aim 2 will examine the molecular and cellular mechanisms mediated by anaphlyatoxins. Aim 3 will define the role of complement in tumor initiation. Completion of this project will provide preclinical data for future clinical trials using pharmacological complement modulators which have been developed for other diseases.
肺癌是男性和女性癌症死亡的主要原因, 在过去的25年里,大多数患者的病情得到了显著改善。逃避免疫攻击是一种 是癌症的标志,由癌细胞和肿瘤微环境之间的相互作用介导 (TME)。已建立的肿瘤,包括肺癌,采用各种策略来阻止免疫攻击, 靶向这些途径已显示出作为治疗方法的前景。虽然研究较少,但也有可能 免疫逃避对于肿瘤的发生至关重要。补体系统是先天免疫系统的组成部分, 免疫系统,它与适应性免疫系统接口。补体激活通过 三种主要途径:经典途径、替代途径和凝集素途径。所有这些都引发了一系列 在C3 b与靶细胞表面的共价固定中会聚的蛋白水解级联。沉积的C3 b 导致C5转化酶的形成,其裂解C5以产生C5 a,并最终形成C5 b- 9,命名为膜攻击复合物(MAC),其可引起靶细胞裂解。c3 a和c5 a (过敏毒素),补体激活的副产物,是结合到受体上的炎症介质, TME的多个细胞。最初提出,补体的激活是由抗体结合至 癌细胞将通过MAC依赖性杀死癌细胞来抑制癌症。然而,我们最近的研究表明, 小组和其他人已经表明,过敏毒素(C3 a/C5 a)通过作用于 TME参与免疫逃避途径。使用一种新的非小细胞原位免疫活性模型 肺癌(NSCLC),我们已经表明,补体在肺肿瘤中被激活,抑制补体 无论是基因上还是肿瘤学上都能阻止肿瘤的发展。然而,补体是如何被激活的, 它如何调节肿瘤进展还不清楚。这个项目将回答这些问题使用 与不同致癌驱动因素相关的肺癌起始和进展模型。中心前提 补体的活化直接导致肺癌的发生, 通过对先天免疫细胞的直接作用导致免疫抑制而进展。的MPI 该项目是具有肺癌生物学经验的研究人员(Nemenoff)和 补充生物学(瑟曼)。我们将采用一组创新的遗传小鼠模型,以及 评估补体在改变TME中的作用的新方法。提出了三个具体目标。 目的1将确定补体激活在已建立的肺肿瘤的机制。目标2将审查 由anaphlyatoxins介导的分子和细胞机制。目标3将定义补体在 肿瘤起始。该项目的完成将为未来的临床试验提供临床前数据, 已开发用于其它疾病的药理学补体调节剂。

项目成果

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RAPHAEL A. NEMENOFF其他文献

RAPHAEL A. NEMENOFF的其他文献

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{{ truncateString('RAPHAEL A. NEMENOFF', 18)}}的其他基金

Colorado HNC SPORE Career Enhancement Program
科罗拉多州 HNC SPORE 职业提升计划
  • 批准号:
    10704608
  • 财政年份:
    2021
  • 资助金额:
    $ 39.49万
  • 项目类别:
Colorado HNC SPORE Career Enhancement Program
科罗拉多州 HNC SPORE 职业提升计划
  • 批准号:
    10477471
  • 财政年份:
    2021
  • 资助金额:
    $ 39.49万
  • 项目类别:
The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis
肺肿瘤微环境:常驻肺血管祖细胞在癌症进展和转移中的作用
  • 批准号:
    10097362
  • 财政年份:
    2020
  • 资助金额:
    $ 39.49万
  • 项目类别:
The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis
肺肿瘤微环境:常驻肺血管祖细胞在癌症进展和转移中的作用
  • 批准号:
    10308484
  • 财政年份:
    2020
  • 资助金额:
    $ 39.49万
  • 项目类别:
Effects of Complement on the Tumor Microenvironment in Lung Cancer
补体对肺癌肿瘤微环境的影响
  • 批准号:
    10521237
  • 财政年份:
    2018
  • 资助金额:
    $ 39.49万
  • 项目类别:
Effects of Complement on the Tumor Microenvironment in Lung Cancer
补体对肺癌肿瘤微环境的影响
  • 批准号:
    10053335
  • 财政年份:
    2018
  • 资助金额:
    $ 39.49万
  • 项目类别:
Eicosanoids in Lung Cancer: Progression and Metastasis
类二十烷酸在肺癌中的作用:进展和转移
  • 批准号:
    8786871
  • 财政年份:
    2013
  • 资助金额:
    $ 39.49万
  • 项目类别:
Eicosanoids in Lung Cancer: Progression and Metastasis
类二十烷酸在肺癌中的作用:进展和转移
  • 批准号:
    8446051
  • 财政年份:
    2013
  • 资助金额:
    $ 39.49万
  • 项目类别:
Eicosanoids in Lung Cancer: Progression and Metastasis
类二十烷酸在肺癌中的作用:进展和转移
  • 批准号:
    9197948
  • 财政年份:
    2013
  • 资助金额:
    $ 39.49万
  • 项目类别:
Eicosanoids in Lung Cancer: Progression and Metastasis
类二十烷酸在肺癌中的作用:进展和转移
  • 批准号:
    8598081
  • 财政年份:
    2013
  • 资助金额:
    $ 39.49万
  • 项目类别:

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