Targeting the innate immune response in HNSCC

免疫治疗有望改善头颈部鳞状细胞癌的疾病结局 （HNSCC）患者。HNSCC是全球第六大常见癌症，是一种致命和毁容的疾病， 仅在美国，2021年就有超过54，000例病例和10，850例死亡。病例持续 上升，部分原因是人乳头瘤病毒（HPV）相关口咽癌的增加。当前 手术、化疗和放疗的标准治疗方案与显著的 发病率和生活质量下降，5年生存率不高。免疫疗法提供了新的 HNSCC患者的选择; T细胞检查点抑制剂治疗导致20-30%的HNSCC患者的生存率提高， 治疗的病人。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 这种疾病需要靶向免疫逃逸的其它机制的治疗方法。我们 研究表明，免疫抑制性肿瘤相关巨噬细胞（TAMs）促进HNSCC免疫 逃跑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肿瘤中积累，在促进免疫应答方面发挥不同作用。 抑制，但也提供了可以靶向促进肿瘤根除的明显弱点。靶向 增殖途径抑制TRM积累和肿瘤进展，同时靶向骨髓细胞 特异性磷脂酰肌醇-4，5-二磷酸3-激酶亚型γ（PI 3 Kg）抑制BMDM 积累此外，PI 3 Kg抑制促进促炎性巨噬细胞极化， 与检查点抑制剂协同作用，以增强细胞毒性CD 8 + T细胞的募集和活化，导致 肿瘤根除这些结果表明，靶向TAMs以及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，PI 3 Kg 在HNSCC患者中，拮抗作用刺激增强的T细胞募集和活化。因此，我们建议 测试总体假设，即阻断巨噬细胞积聚和免疫应答的治疗策略， 抑制将改善HNSCC疾病的治疗结果。这项建议的具体目标是： 鉴定和靶向控制HNSCC肿瘤中巨噬细胞积聚的机制。2)以确定如何 可以利用巨噬细胞可塑性来抑制HNSCC肿瘤进展。3)开发新的免疫系统 HNSCC疾病的治疗策略和免疫生物标志物。

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.