Investigating Macrophage Molecular and Functional Diversity in Tumor Immunity

研究肿瘤免疫中巨噬细胞的分子和功能多样性

基本信息

  • 批准号:
    10558483
  • 负责人:
  • 金额:
    $ 68.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-02-01 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Macrophages (MF) are one of the largest immune cell components of tumor lesions, where their numbers can even exceed cancer cells. MF play a key role in shaping the composition of the tumor microenvironment (TME), the modulation of tumor innate and adaptive immunity, and the response to cancer immunotherapy. Because of their critical roles, MF are an important target for cancer treatment. However, modulating tumor- associated MF has proved extremely difficult. This is in large part because we still do not have a complete understanding of the tumor MF compartment. In order to develop ways to modulate tumor MF and promote cancer immunity, it is vital we gain a deeper understanding of the molecular and functional diversity of MF in their tissue context. Using mass cytometry (CyTOF) and single cell RNA-seq (scRNA-seq), we initiated deep characterization of the immune composition of early human non-small cell lung carcinomas (NSCLC). We uncovered evidence of multiple distinct MF populations enriched in human tumors. Notably, related MF clusters were also identified in mice lung cancer lesions. Using fate mapping and scRNA-seq, we discovered these discrete MF populations differ in developmental origin and have a distinct distribution in the TME. When the different subsets of MF were depleted, tumor growth was impaired, but the alterations in TME differed, suggesting distinct mechanisms of activity. Based on our findings, we hypothesize that the unique subsets of MF have differential molecular states and mediate differential contributions to tumor growth, organization, immunity, and response to PD1 blockade. To address our hypothesis, we will: (1) comprehensively map the MF compartment of human lung tumors, at the single cell level and with spatial resolution, at baseline and during treatment with PD1 blockade, in NSCLC patients enrolled in a neoadjuvant immunotherapy clinical trial, (2) assess the functional contribution of distinct MF subsets to tumor tissue remodeling and immune cell dynamics in the TME, and (3) determine the contribution of distinct MF subsets to lung tumor immunity. We will also (4) investigate the function and activity of a specific cell surface receptor, Trem2, which we found to be exclusively expressed on monocyte-derived MF in both human and mouse lung tumors, and whose knockout impaired lung tumor growth similar to MF depletion; suggesting an important and potentially targetable molecule in MF control of tumor growth. The outcome of these studies will (i) uncover the molecular and functional diversity of the MF compartment of human lung tumors, (ii) determine how distinct MF subsets, and MF-specific genes, influence tumor growth, the TME state, and tumor immunity, and (iii) provide insight into to how MF subsets influence, and are influenced by, PD1 blockade in human NSCLC. These studies have the potential to help us understand some of the factors that contribute to tumor response and resistance to immune editing, and aid in the further development and clinical use of cancer immunotherapy strategies.
项目摘要 巨噬细胞(MF)是肿瘤病变中最大的免疫细胞成分之一,它们的数量 甚至超过癌细胞。MF在形成肿瘤微环境的组成中起关键作用 (TME)肿瘤先天免疫和适应性免疫的调节,以及对癌症免疫治疗的应答。 由于它们的关键作用,MF是癌症治疗的重要靶点。然而,调节肿瘤- 相关联的MF被证明是极其困难的。这在很大程度上是因为我们仍然没有一个完整的 了解肿瘤MF区室。为了开发调节肿瘤MF和促进肿瘤生长的方法, 癌症免疫,这是至关重要的,我们获得了更深入的了解MF的分子和功能多样性, 他们的组织背景 使用质谱仪(CyTOF)和单细胞RNA-seq(scRNA-seq),我们开始了对 早期人类非小细胞肺癌(NSCLC)的免疫组成。我们发现了 在人类肿瘤中富集的多种不同MF群体。值得注意的是,相关的MF集群也被确定在 小鼠肺癌病变。使用命运作图和scRNA-seq,我们发现了这些离散的MF群体, 不同的发育起源,并有一个独特的分布在TME。当MF的不同子集被 耗尽,肿瘤生长受损,但TME的改变不同,表明不同的机制, 活动基于我们的发现,我们假设MF的独特子集具有不同的分子状态 并介导对肿瘤生长、组织、免疫和对PD 1阻断的应答的不同贡献。 为了解决我们的假设,我们将:(1)全面绘制人肺肿瘤的MF区室,在 NSCLC患者在基线和PD 1阻断治疗期间的单细胞水平和空间分辨率 参加新辅助免疫治疗临床试验的患者,(2)评估不同免疫治疗的功能贡献, MF亚群对TME中肿瘤组织重塑和免疫细胞动力学的影响,以及(3)确定MF亚群对TME中肿瘤组织重塑和免疫细胞动力学的贡献。 不同MF亚群对肺肿瘤免疫的影响。我们还将(4)研究一个特定的功能和活动, 细胞表面受体Trem 2,我们发现它只表达在单核细胞衍生的MF上, 人和小鼠肺肿瘤,其敲除损害肺肿瘤生长,类似于MF耗竭; 这表明在肿瘤生长的MF控制中是重要的和潜在的靶向分子。 这些研究的结果将(i)揭示MF隔室的分子和功能多样性 (ii)确定不同的MF亚群和MF特异性基因如何影响肿瘤生长, TME状态和肿瘤免疫,以及(iii)提供对MF亚群如何影响和被影响的洞察 通过PD 1阻断在人NSCLC中的作用。这些研究有可能帮助我们理解一些因素 这有助于肿瘤反应和对免疫编辑的抵抗,并有助于进一步发展, 癌症免疫治疗策略的临床应用。

项目成果

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Brian D Brown其他文献

Cancer vaccines and the future of immunotherapy
  • DOI:
    10.1016/s0140-6736(25)00553-7
  • 发表时间:
    2025-07-12
  • 期刊:
  • 影响因子:
    88.500
  • 作者:
    Orrin Pail;Matthew J Lin;Theodora Anagnostou;Brian D Brown;Joshua D Brody
  • 通讯作者:
    Joshua D Brody

Brian D Brown的其他文献

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{{ truncateString('Brian D Brown', 18)}}的其他基金

Spatial functional genomics to identify regulators of the tumor microenvironment and cancer immunity
空间功能基因组学识别肿瘤微环境和癌症免疫的调节因子
  • 批准号:
    10720979
  • 财政年份:
    2023
  • 资助金额:
    $ 68.46万
  • 项目类别:
Deciphering the molecular control of intratumoral dendritic cells
破译瘤内树突状细胞的分子控制
  • 批准号:
    10331052
  • 财政年份:
    2021
  • 资助金额:
    $ 68.46万
  • 项目类别:
Deciphering the molecular control of intratumoral dendritic cells
破译瘤内树突状细胞的分子控制
  • 批准号:
    10559621
  • 财政年份:
    2021
  • 资助金额:
    $ 68.46万
  • 项目类别:
Development of a platform for spatial functional genomics
空间功能基因组学平台的开发
  • 批准号:
    10471387
  • 财政年份:
    2020
  • 资助金额:
    $ 68.46万
  • 项目类别:
Development of a platform for spatial functional genomics
空间功能基因组学平台的开发
  • 批准号:
    10031205
  • 财政年份:
    2020
  • 资助金额:
    $ 68.46万
  • 项目类别:
Development of a platform for spatial functional genomics
空间功能基因组学平台的开发
  • 批准号:
    10250339
  • 财政年份:
    2020
  • 资助金额:
    $ 68.46万
  • 项目类别:
Development of a platform for spatial functional genomics
空间功能基因组学平台的开发
  • 批准号:
    10640950
  • 财政年份:
    2020
  • 资助金额:
    $ 68.46万
  • 项目类别:
T cell-tissue interaction models
T细胞-组织相互作用模型
  • 批准号:
    9205538
  • 财政年份:
    2016
  • 资助金额:
    $ 68.46万
  • 项目类别:
T cell-tissue interaction models
T细胞-组织相互作用模型
  • 批准号:
    9107663
  • 财政年份:
    2016
  • 资助金额:
    $ 68.46万
  • 项目类别:
Modulating Immunity to Nucleic Acids and Inducing Tolerance by Gene Transfer
通过基因转移调节核酸免疫并诱导耐受
  • 批准号:
    8886697
  • 财政年份:
    2015
  • 资助金额:
    $ 68.46万
  • 项目类别:
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