Targeting the innate immune response in HNSCC

针对 HNSCC 的先天免疫反应

• 批准号: 9980195
• 负责人: Judith A VARNER
• 金额: $ 46.83万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980195
• 关键词: Animal Model; Automobile Driving; Biological; Blood Circulation; CD8-Positive T-Lymphocytes; Cancer Etiology; Cessation of life; Chemotherapy and/or radiation; Clinical; Complex; Country; Disease; FRAP1 gene; Gene Expression Profile; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Markers; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Inflammatory; Innate Immune Response; Interferon Type II; Interleukin-10; Interleukin-12; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Molecular; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Nivolumab; Patient-Focused Outcomes; Patients; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphotransferases; Proteins; Role; Sampling; Signal Pathway; Signal Transduction; System; T cell response; T cell therapy; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tumor-associated macrophages; United States; Woman; animal tissue; anti-PD-1; anti-tumor immune response; arginase; cancer therapy; combat; cytotoxic; cytotoxic CD8 T cells; immunogenic; improved; improved outcome; macrophage; malignant mouth neoplasm; malignant oropharynx neoplasm; men; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; phase III trial; polarized cell; predictive signature; recruit; response; standard of care; targeted agent; therapeutic target; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Abstract The immune system is a complex but highly plastic biological defense system that normally protects the host against infection and damage. However, in some disease states, such as cancer, the usually well-orchestrated immune response fails to protect the host and instead exacerbates disease. Because the immune system is highly plastic, however, novel therapeutics may be able to restore normal immune responses that combat cancer. There is a critical need to develop novel therapies for oral cancers, such as head and neck squamous cell carcinoma (HNSCC), a deadly and disfiguring disease that accounts for an estimated 59,340 cases (43,390 men and 15,950 women) and 12,290 deaths each year in the United States. The incidence of HNSCC is rapidly rising in the United States and worldwide, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. While current immune therapies hold new promise for the treatment of cancer, the checkpoint inhibitor nivolumab (anti-PD-1) recently demonstrated only modest single agent activity in recurrent/metastatic HNSCC, as one-year survival and response rates were only 36% and 13%, respectively, in a Phase 3 trial. Improved therapeutic approaches that target additional mechanisms of immune escape in combination with checkpoint inhibitors could hold promise for this disease. Our recent studies (Nature 2016) showed that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune escape. We found that two macrophage proteins, phosphatidylinositol-4,5-bisphosphate 3-kinase gamma PI3Kγ inhibition repolarized macrophages and synergized with anti-PD-1 to enhance recruitment and activation of IFNγ+ cytotoxic CD8+ T cells. These results indicate that therapeutic strategies that target TAMs as well as T cell checkpoints could improve HNSCC patient outcomes. We propose to test the overall hypothesis that therapeutic strategies that block macrophage-mediated immune suppression will synergize with T cell targeted therapeutics to improve outcomes in HNSCC disease. The specific aims of this proposal are: 1) To determine how immune suppressive myeloid cells are recruited to HNSCC tumors. 2) To identify how myeloid cell polarization is controlled during HNSCC tumor progression. 3) To identify novel immune therapeutic strategies and immune biomarkers for HNSCC disease.

摘要 免疫系统是一个复杂但可塑性很强的生物防御系统，通常会保护宿主 防止感染和损伤。然而，在某些疾病状态下，如癌症，通常精心策划的 免疫反应不能保护宿主，反而使疾病恶化。因为免疫系统 然而，高度可塑性，新的治疗方法可能能够恢复正常的免疫反应， 癌迫切需要开发用于口腔癌（如头颈鳞状上皮癌）的新疗法。 细胞癌（HNSCC），一种致命和毁容的疾病，估计有59，340例 (43在美国，每年有15，390名男性和15，950名女性）和12，290人死亡。HNSCC的发病率 在美国和世界范围内迅速上升，部分原因是人乳头瘤病毒（HPV）的增加 相关的口咽癌。虽然目前的免疫疗法为癌症治疗带来了新的希望， 检查点抑制剂纳武单抗（抗PD-1）最近在 复发/转移性HNSCC，1年生存率和缓解率分别仅为36%和13%， 在第三阶段试验中。针对免疫逃逸的其他机制的改进的治疗方法， 与检查点抑制剂的组合可以为这种疾病带来希望。我们最近的研究（Nature 2016） 显示免疫抑制性肿瘤相关巨噬细胞（TAMs）促进HNSCC免疫逃逸。 我们发现两种巨噬细胞蛋白，磷脂酰肌醇-4，5-二磷酸3-激酶γ PI 3 K γ， 抑制使巨噬细胞复极化并与抗PD-1协同作用以增强巨噬细胞的募集和活化。 IFNγ+细胞毒性CD 8 + T细胞。这些结果表明，靶向TAMs以及T细胞的治疗策略， 细胞检查点可以改善HNSCC患者的预后。我们建议测试的总体假设， 阻断巨噬细胞介导的免疫抑制的治疗策略将与靶向T细胞的治疗策略协同作用。 改善HNSCC疾病结局的治疗方法。本建议的具体目标是：1）确定 免疫抑制性骨髓细胞如何被募集到HNSCC肿瘤中。2)为了确定骨髓细胞 极化在HNSCC肿瘤进展期间受到控制。3)确定新型免疫治疗策略 和HNSCC疾病的免疫生物标志物。