Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1

通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力

基本信息

  • 批准号:
    9980667
  • 负责人:
  • 金额:
    $ 47.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-05 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT Despite significant clinical breakthroughs in anticancer immunotherapy, the efficacy of current immunotherapies in breast cancer is modest. Only a small fraction of breast cancer patients have a clinical response; complete responses to these agents are exceedingly rare. The underlying mechanisms of tissue- specific immune regulation in breast cancer remains to be elucidated. Furthermore, how comorbidities such as obesity influence antitumor immunity in breast cancer is even less understood. Discoidin domain receptor 1 (DDR1) is a collagen receptor with an intrinsic tyrosine kinase activity. High DDR1 expression in breast cancer is associated with poor patient outcomes and attenuated antitumor immunity. We found complex tumor-promoting actions for both tumor and adipose DDR1 in the breast tumor microenvironment. Tumor DDR1 suppresses antitumor immunity, whereas adipose DDR1 is required for diet- induced obesity, tumor-promoting cytokine production, and immune modulation. Our preliminary data further indicate that the shed extracellular domain of DDR1 alone is sufficient for its functions in tumor and adipose cells, which has not previously been reported. We therefore hypothesize that DDR1 in the breast tumor microenvironment promotes tumor progression by dampening antitumor immunity, enabling adiposity, and abetting immune-adipose cell-tumor crosstalk. We predict that blocking kinase-independent DDR1 signals can boost antitumor immunity and response to anticancer immunotherapies, especially in patients with obesity. To test this hypothesis, in this R01 application, we will determine how tumor DDR1 suppresses antitumor immunity (Aim 1), how adipose DDR1 contributes to obesity-associated cancer progression (Aim 2), and how DDR1 carries out its immune-suppressive functions independent of its kinase activity (Aim 3). With combined expertise in cancer biology, tumor immunology, and clinical oncology, our multidisciplinary team is well positioned to validate our novel hypothesis. The fact that DDR1 has distinct functions in different cell compartments of the breast tumor microenvironment underscores the complexity of tumor-stromal interactions. By investigating tumor and adipose DDR1 in an integrative and comprehensive manner as proposed here, we will fill major gaps of knowledge about tumor-initiated immune suppression and obesity-associated comorbid effects. Given the adipocyte-rich tumor microenvironment in breast cancer and the growing numbers of patients with obesity and breast cancer, our proposed studies address an unmet clinical need and promise to inform the development of new strategies to enhance antitumor immunity for breast cancer patients, especially for those with obesity. !
摘要

项目成果

期刊论文数量(0)
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Rong Li其他文献

Rong Li的其他文献

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{{ truncateString('Rong Li', 18)}}的其他基金

Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10436938
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10524141
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10640210
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10524142
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10737815
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Supplement to Support Research Training in HDAC11 and Cancer
支持 HDAC11 和癌症研究培训的补充品
  • 批准号:
    10380397
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力
  • 批准号:
    10395597
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10737814
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Regulation of anti-tumor immunity by HDAC11
HDAC11 调节抗肿瘤免疫
  • 批准号:
    10174876
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:
Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力
  • 批准号:
    10159224
  • 财政年份:
    2020
  • 资助金额:
    $ 47.69万
  • 项目类别:

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