Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

视黄酸对肿瘤微环境中抗原呈递细胞的调节

基本信息

  • 批准号:
    10307073
  • 负责人:
  • 金额:
    $ 36.83万
  • 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:
    2018-12-03 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary Evading immune responses is a hallmark of cancer. The `tumor-immunity cycle' begins with the processing of tumor-associated proteins by dendritic cells (DC), which initiate a T-cell response in draining lymph nodes, followed by the trafficking of these anti-tumor T cells into the tumor to mediate tumor lysis. Tumors can block one or more steps of this cycle to evade immune responses. The therapeutic potential of targeting such immune-evasion pathways is highlighted by the clinical success of immune checkpoint inhibitors that alleviates T cell suppression in cancer. However, tumor-reactive T cells are not generated in most solid tumors, which limit the utility of immune checkpoint inhibitors. A major reason for this failure to generate anti-tumor T cells is the paucity and dysfunction of DCs in the tumor microenvironment (TME). While DCs are rare inside tumors, a closely related cell type, macrophages, are abundant. In contrast to DCs, tumor-associated macrophages (TAMs) are immunosuppressive and promote tumor progression. Both DCs and TAMs can originate from monocytes but there is a major knowledge gap in our understanding of why monocytes preferentially differentiate into immunosuppressive TAMs but not immunostimulatory DCs in solid tumors. Our long-term interest is to understand the development and differentiation of macrophages and DCs in the TME with the overarching goal of targeting these cells for cancer immunotherapy. I previously developed powerful genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as mouse models to study antigen-presenting cells. Using these tools in my laboratory, I recently discovered that tumor cell-derived retinoic acid blocks DC but promotes TAM differentiation from monocytes. Furthermore, I have found that the cytokine IL13 promotes RA production in tumor cells. Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the generation of immunostimulatory DCs from TME monocytes. I posit that this is a major pathway of immune evasion in solid tumors. Our two specific aims will delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1) and uncover how IL13 controls RA production in TME (Aim 2). We will also examine the value of targeting this pathway for tumor immunotherapy. This work will have significant impact on our understanding of immunomodulation in solid tumors and establish a new approach in solid tumor immunotherapy based on targeting RA signaling in APCs. Our work is innovative because it will open new avenues of research into the role of retinoid signaling in APC differentiation and tumor immunity.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Malay Haldar其他文献

Malay Haldar的其他文献

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{{ truncateString('Malay Haldar', 18)}}的其他基金

Delineating how nucleic acid sensing in tumor cells regulate anti-tumor immune responses
描述肿瘤细胞中的核酸传感如何调节抗肿瘤免疫反应
  • 批准号:
    10626284
  • 财政年份:
    2023
  • 资助金额:
    $ 36.83万
  • 项目类别:
Role of glutamine metabolism in Dendritic Cell Development
谷氨酰胺代谢在树突状细胞发育中的作用
  • 批准号:
    10735230
  • 财政年份:
    2023
  • 资助金额:
    $ 36.83万
  • 项目类别:
Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid
视黄酸对肿瘤微环境中抗原呈递细胞的调节
  • 批准号:
    10524742
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid
视黄酸对肿瘤微环境中抗原呈递细胞的调节
  • 批准号:
    10051410
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION
组织特异性巨噬细胞分化的代谢控制
  • 批准号:
    9303241
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION
组织特异性巨噬细胞分化的代谢控制
  • 批准号:
    9074750
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION
组织特异性巨噬细胞分化的代谢控制
  • 批准号:
    8566784
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION
组织特异性巨噬细胞分化的代谢控制
  • 批准号:
    8663189
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:

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