TOX-driven CD8 T cell differentiation and dysfunction in tumors

TOX驱动的肿瘤中CD8 T细胞分化和功能障碍

基本信息

  • 批准号:
    10586679
  • 负责人:
  • 金额:
    $ 61.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY CD8 T cells specific for cancer cells are found within human tumors, but despite their presence, tumors progress, suggesting that T cells become unresponsive. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell dysfunction. We previously demonstrated that T cells in tumors enter an epigenetically encoded dysfunction state that becomes resistant to therapeutic reprogramming and found that TOX, a DNA-binding protein, is a key regulator enforcing the dysfunctional state. The factors that drive TOX expression, and how TOX precisely establishes the dysfunction program remain largely unknown. TCR signal strength impacts T cell differentiation, and while we know that antigen chronicity is a key driver of TOX-driven T cell dysfunction, we do not know how signal strength of chronic tumor antigen impacts TOX-driven dysfunction and amenability to immunotherapeutic reprogramming. In this application, we will determine how signal strength regulates TOX and TOX-driven dysfunction programs in mouse and human tumors, ask how TOX induces and maintains dysfunction, and target TOX and its downstream mediators to uncover the mechanisms underlying dysfunction imprinting. To achieve these goals, we will utilize clinically relevant genetic cancer mouse models and track T cells longitudinally within progressing tumors while encountering tumor antigens with varying signal strength. We will employ transcriptomic and epigenomic methods and innovative protein degradation strategies to determine what controls TOX, how TOX induces and/or maintains dysfunction, and how TOX downstream mediators regulate the epigenetic programs associated with plasticity and dysfunction imprinting. We will leverage human neoantigen- specific tumor-infiltrating T cell resources to understand how TCR signal strength determines TOX- dependent molecular signatures and functional states of T cells in human tumors. Importantly, we will test and design strategies to target TOX and TOX downstream mediators to improve cancer immunotherapy.
PROJECT SUMMARY CD8 T cells specific for cancer cells are found within human tumors, but despite their presence, tumors progress, suggesting that T cells become unresponsive. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell dysfunction. We previously demonstrated that T cells in tumors enter an epigenetically encoded dysfunction state that becomes resistant to therapeutic reprogramming and found that TOX, a DNA-binding protein, is a key regulator enforcing the dysfunctional state. The factors that drive TOX expression, and how TOX precisely establishes the dysfunction program remain largely unknown. TCR signal strength impacts T cell differentiation, and while we know that antigen chronicity is a key driver of TOX-driven T cell dysfunction, we do not know how signal strength of chronic tumor antigen impacts TOX-driven dysfunction and amenability to immunotherapeutic reprogramming. In this application, we will determine how signal strength regulates TOX and TOX-driven dysfunction programs in mouse and human tumors, ask how TOX induces and maintains dysfunction, and target TOX and its downstream mediators to uncover the mechanisms underlying dysfunction imprinting. To achieve these goals, we will utilize clinically relevant genetic cancer mouse models and track T cells longitudinally within progressing tumors while encountering tumor antigens with varying signal strength. We will employ transcriptomic and epigenomic methods and innovative protein degradation strategies to determine what controls TOX, how TOX induces and/or maintains dysfunction, and how TOX downstream mediators regulate the epigenetic programs associated with plasticity and dysfunction imprinting. We will leverage human neoantigen- specific tumor-infiltrating T cell resources to understand how TCR signal strength determines TOX- dependent molecular signatures and functional states of T cells in human tumors. Importantly, we will test and design strategies to target TOX and TOX downstream mediators to improve cancer immunotherapy.

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Andrea Schietinger其他文献

Andrea Schietinger的其他文献

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{{ truncateString('Andrea Schietinger', 18)}}的其他基金

Autoimmune Stem-like CD8 T cells in Type 1 Diabetes
1 型糖尿病中的自身免疫干细胞样 CD8 T 细胞
  • 批准号:
    10736295
  • 财政年份:
    2023
  • 资助金额:
    $ 61.7万
  • 项目类别:
Spatiotemporal regulation of T cell fate decisions in cancer
癌症中 T 细胞命运决定的时空调控
  • 批准号:
    9350820
  • 财政年份:
    2017
  • 资助金额:
    $ 61.7万
  • 项目类别:
Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis
早期肿瘤发生中肿瘤特异性 T 细胞状态动态和异质性
  • 批准号:
    9980808
  • 财政年份:
    2016
  • 资助金额:
    $ 61.7万
  • 项目类别:
Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens
T 细胞对肿瘤抗原耐受的分子和表观遗传程序
  • 批准号:
    9205491
  • 财政年份:
    2015
  • 资助金额:
    $ 61.7万
  • 项目类别:
Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens
T 细胞对肿瘤抗原耐受的分子和表观遗传程序
  • 批准号:
    8975841
  • 财政年份:
    2015
  • 资助金额:
    $ 61.7万
  • 项目类别:
Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens
T 细胞对肿瘤抗原耐受的分子和表观遗传程序
  • 批准号:
    8424846
  • 财政年份:
    2013
  • 资助金额:
    $ 61.7万
  • 项目类别:
Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens
T 细胞对肿瘤抗原耐受的分子和表观遗传程序
  • 批准号:
    8601299
  • 财政年份:
    2013
  • 资助金额:
    $ 61.7万
  • 项目类别:

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