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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：
Judith A VARNER
金额：
$ 49.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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

来源：
https://reporter.nih.gov/project-details/10586476
关键词：
Alcohol consumption Automobile Driving B-Lymphocytes Biological Markers Blood Circulation Bone Marrow CD8-Positive T-Lymphocytes Cancer Etiology Cessation of life Chemotherapy and/or radiation Clinical Trials Country Developing Countries Disease Disease Outcome Elements Funding Genetic Transcription Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Healthcare Human Papillomavirus Human papilloma virus infection Immune Immune checkpoint inhibitor Immunologic Markers Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Inflammatory Innate Immune Response Interleukin-10 Interleukin-12 Malignant Neoplasms Mediating Molecular Morbidity - disease rate Mus Myeloid Cells Natural Killer Cells Operative Surgical Procedures PD-1 inhibitors Pathway interactions Patient Monitoring Patient Selection Patient-Focused Outcomes Patients Phase Phase II Clinical Trials Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Play Protein Isoforms Proto-Oncogene Protein c-kit Quality of life Radiation therapy Regimen Resistance Role Signal Transduction Survival Rate T cell response T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Agents Tissues Tobacco use Tumor Immunity Tumor-associated macrophages United States Woman antagonist anti-PD-1 anti-tumor immune response arginase cytotoxic cytotoxic CD8 T cells improved inhibitor therapy macrophage malignant oropharynx neoplasm men mortality novel novel therapeutic intervention novel therapeutics patient biomarkers recruit response biomarker secondary lymphoid organ targeted agent therapy outcome tool trafficking treatment strategy tumor tumor eradication tumor growth tumor microenvironment tumor progression

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