Targeting the innate immune response in HNSCC

摘要 免疫系统是一个复杂但高度可塑性的生物防御系统，通常保护宿主 防止感染和破坏。然而，在一些疾病状态，如癌症，通常是精心策划的 免疫反应不能保护宿主，反而会加剧疾病。因为免疫系统是 然而，高度可塑性的新疗法可能能够恢复正常的免疫反应， 癌症。迫切需要开发新的口腔癌症治疗方法，如头颈部鳞状细胞癌。 细胞癌(HNSCC)，一种致命的毁容疾病，估计占59,340例 (43,390名男性和15,950名女性)，美国每年有12,290人死亡。人非小细胞肺癌的发病率 在美国和世界范围内迅速上升，部分原因是人类乳头瘤病毒(HPV)的增加 相关的口咽癌。虽然目前的免疫疗法为癌症的治疗带来了新的希望， 检查点抑制剂nivolumab(抗PD-1)最近仅显示出适度的单药活性 复发/转移性HNSCC，一年生存率和缓解率分别为36%和13%， 在第三阶段试验中。以其他免疫逃逸机制为靶点的改进治疗方法 与检查点抑制剂联合使用可能会为这种疾病带来希望。我们最近的研究(《自然》2016) 研究表明，免疫抑制的肿瘤相关巨噬细胞(TAMs)促进HNSCC的免疫逃逸。 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 抑制复极化巨噬细胞并与抗PD-1协同增强巨噬细胞的募集和激活 干扰素γ+细胞毒性CD8T细胞。这些结果表明，针对TAMs和T的治疗策略 细胞检查点可以改善HNSCC患者的预后。我们建议检验总体假设，即 阻断巨噬细胞介导的免疫抑制的治疗策略将与T细胞靶向协同作用 改善HNSCC疾病预后的治疗方法。该提案的具体目的是：1)确定 免疫抑制髓系细胞如何被招募到HNSCC肿瘤。2)鉴定髓系细胞如何 极化在HNSCC肿瘤进展过程中受到控制。3)寻找新的免疫治疗策略 以及HNSCC疾病的免疫生物标记物。

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.