Targeting the innate immune response in HNSCC

针对 HNSCC 的先天免疫反应

• 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
• 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

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疾病结局 (HNSCC)患者。HNSCC是世界上第六种最常见的癌症，是一种致命和毁容的疾病 仅在美国，2021年就造成了54,000多例病例和10,850人死亡。案件仍在继续 上升的部分原因是与人类乳头瘤病毒(HPV)相关的口咽癌的增加。海流 手术、化疗和放射治疗的标准治疗方案与显著相关 发病率和生活质量下降，仅有适度的5年存活率。免疫疗法提供了新的 HNSCC患者的选择；T细胞检查点抑制剂的治疗使20%-30%的患者的存活率增加 治疗过的病人。然而，大多数HNSCC患者对T细胞检查点抑制剂具有耐药性。改进 这种疾病需要针对其他免疫逃逸机制的治疗方法。我们的 研究表明，免疫抑制的肿瘤相关巨噬细胞(TAMs)促进HNSCC免疫 逃走。我们发现组织驻留巨噬细胞(TRM)和骨髓源性巨噬细胞 (BMDM)在HPV+和HPV-HNSCC肿瘤中积聚，在促进免疫方面发挥着不同的作用 抑制，但也提供了明显的脆弱性，可以有针对性地促进肿瘤根除。瞄准 以髓系细胞为靶点的增殖途径抑制TRM积聚和肿瘤进展 特异性磷脂酰肌醇-4，5-二磷酸3-激酶异构体γ(PI3Kg)抑制BMDM 积累。此外，抑制PI3Kg可促进促炎巨噬细胞极化 与检查点抑制剂协同作用，增强细胞毒性CD8+T细胞的招募和激活，导致 肿瘤根除。这些结果表明，针对TAMs和T细胞的治疗策略 检查点可以改善HNSCC患者的预后。临床试验中的生物标志物研究表明，PI3Kg 拮抗作用可促进HNSCC患者T细胞的募集和活化。因此，我们建议 测试阻止巨噬细胞聚集和免疫的治疗策略的总体假设 抑制将改善HNSCC疾病的治疗结果。这项建议的具体目的是：1) 识别和靶向控制HNSCC肿瘤中巨噬细胞聚集的机制。2)确定如何 巨噬细胞的可塑性可以被利用来抑制HNSCC肿瘤的进展。3)开发新型免疫 HNSCC疾病的治疗策略和免疫生物标志物。