Targeting the innate immune response in HNSCC

针对 HNSCC 的先天免疫反应

基本信息

  • 批准号:
    10586476
  • 负责人:
  • 金额:
    $ 49.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-15 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

Immune therapy holds great promise to improve disease outcomes for head and neck squamous cell carcinoma (HNSCC) patients. The sixth most common cancer worldwide, HNSCC is a deadly and disfiguring disease that accounted for more than 54,000 cases and 10,850 deaths in 2021 in the United States alone. Cases continue to rise, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. The current standard therapeutic regimens of surgery, chemotherapy and radiation therapy are associated with significant morbidity and loss of quality of life with only modest 5-year survival rates. Immune therapy has offered new options for HNSCC patients; treatment with T cell checkpoint inhibitors has led to gains in survival for 20-30% of treated patients. However, the majority of HNSCC patients are resistant to T cell checkpoint inhibitors. Improved therapeutic approaches that target additional mechanisms of immune escape are needed for this disease. Our studies show that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune escape. We discovered that both tissue resident macrophages (TRM) and bone marrow derived macrophages (BMDM) accumulate in HPV+ and HPV- HNSCC tumors, where they play distinct roles in promoting immune suppression but also offer distinct vulnerabilities that can be targeted to promote tumor eradication. Targeting proliferation pathways suppressed TRM accumulation and tumor progression while targeting the myeloid cell specific phosphatidylinositol-4,5-bisphosphate 3-kinase isoform gamma (PI3Kg) suppressed BMDM accumulation. Furthermore, PI3Kg inhibition promoted pro-inflammatory macrophage polarization that synergized with checkpoint inhibitors to enhance recruitment and activation of cytotoxic CD8+ T cells, leading to tumor eradication. These results indicated that therapeutic strategies that target TAMs as well as T cell checkpoints could improve HNSCC patient outcomes. Biomarker studies in clinical trials showed that PI3Kg antagonism stimulated enhanced T cell recruitment and activation in HNSCC patients. Therefore, we propose to test the overall hypothesis that therapeutic strategies that block macrophage accumulation and immune suppression will improve therapeutic outcomes in HNSCC disease. The specific aims of this proposal are: 1) To identify and target mechanisms controlling macrophage accumulation in HNSCC tumors. 2) To determine how macrophage plasticity can be harnessed to inhibit HNSCC tumor progression. 3) To develop novel immune therapeutic strategies and immune biomarkers for HNSCC disease.
免疫疗法有望改善头颈部鳞状细胞癌的预后

项目成果

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Judith A VARNER其他文献

Judith A VARNER的其他文献

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{{ truncateString('Judith A VARNER', 18)}}的其他基金

10X Chromium Connect for Single Cell Library Preparations for Translational Research
用于转化研究的单细胞文库制备的 10X Chromium Connect
  • 批准号:
    10430292
  • 财政年份:
    2022
  • 资助金额:
    $ 49.84万
  • 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
  • 批准号:
    9763352
  • 财政年份:
    2017
  • 资助金额:
    $ 49.84万
  • 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
  • 批准号:
    9980195
  • 财政年份:
    2017
  • 资助金额:
    $ 49.84万
  • 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
  • 批准号:
    10216217
  • 财政年份:
    2017
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase in Tumor Progression and Metastasis
PI3激酶在肿瘤进展和转移中的作用
  • 批准号:
    10375512
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
  • 批准号:
    8828127
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
  • 批准号:
    8844128
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase in Tumor Progression and Metastasis
PI3激酶在肿瘤进展和转移中的作用
  • 批准号:
    10116294
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
  • 批准号:
    9516087
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
  • 批准号:
    9033872
  • 财政年份:
    2012
  • 资助金额:
    $ 49.84万
  • 项目类别:

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