人γδT17细胞在肺癌相关炎症及免疫抑制中的作用及机制研究

Lung cancer is the leading cause of cancer deaths worldwide. The initiation, progression and recurrence of lung cancer are closely linked to chronic inflammation. However, the underlying mechanisms of tumor-associated inflammation in the progression of lung cancer remain unclear. Our previous study found that γδT17 cells were the major source of IL-17 in human lung cancer. Further study demonstrated that inflammatory DCs were increased and secreted a large amount of γδT17 cell polarization-related factors in human lung cancer tissues. Therefore, we hypothesize that activated lung cancer infiltrating DCs secrete IL-23 to promote γδT17 cells polarization, which further facilitate MDSCs mediated immunosuppression. Based on our previous study and clinical immune research platform, this project is proposed to uncover the characteristics, biological function, polarization mechanism of human lung cancer infiltrating γδT17 cells in tumor associated-inflammatory microenvironment and their relationship with clinicopathological feature and prognosis of lung cancer. This study shed light on the role and critical regulatory mechanisms of human γδT17 cells in lung cancer associated inflammation and tumor progression. This project fills the blank of the research field regarding the role and mechanism of human γδT17 cells and provides novel ideas for clinical targeted intervention to tumor-associated inflammatory cells or molecules.

肺癌高居人类恶性肿瘤死因之首，其起始、进展均与慢性炎症密切相关。然而，肿瘤相关炎症在肺癌进展中的作用及机制尚不完全清楚。申请者前期研究发现IL-17分泌型γδT细胞(γδT17)是人肺癌组织IL-17的主要来源。进一步研究显示肺癌浸润炎症性树突状细胞(infDCs)显著增高并分泌大量IL-23。据此我们假设，活化的肺癌组织浸润infDCs分泌IL-23促进γδT17极化，进而促进髓系来源抑制细胞(MDSCs)介导的免疫抑制及肿瘤进展。本课题拟在前期研究基础上，对人γδT17在肺癌炎症微环境中的特征、极化机制及生物学功能展开深入的研究，分析肿瘤浸润γδT17与肺癌临床病理特征及预后的关系，由此阐明人γδT17在肺癌相关炎症及肿瘤进展中的作用及其关键调控机制。该项目填补了人γδT17在肺癌相关炎症中的作用及机制研究的空白，也能为靶向肺癌相关炎症及免疫抑制关键细胞(分子)干预提供新的思路。

肿瘤微环境内T细胞耗竭促进肿瘤的发生发展，也为肿瘤免疫治疗提供了潜在干预靶标。本项目以人肺癌为模型，深入探讨肺癌免疫微环境内参与T细胞耗竭的关键性T细胞亚群及其功能特征。本项目首次发现组织特异性CD8+T细胞（Tissue resident memory CD8+T cells，CD8+TRMs）在人肺癌组织显著富集，而非循环CD8+ T细胞。此外与其他CD8+T细胞亚群相比较，肺癌浸润CD8+TRMs细胞具有高度活化及免疫抑制性受体高表达的双重表型。我们首次证明肺癌浸润CD8+TRMs细胞在肺癌浸润PD1+CD8+T细胞中占主导地位，并且PD1+CD8+TRMs细胞在肺癌组织显著增高。同时，我们在转录组层面发现肺癌浸润CD8+TRMs细胞与其他CD8+T细胞亚群相比具有独特的转录组学特征，而且只有肺癌浸润CD8+TRMs细胞存在免疫耗竭相关基因显著增高。以上原创性研究成果揭示了人肺癌微环境内T细胞免疫耗竭的CD8+TRMs细胞偏好性，提示肿瘤相关T细胞免疫耗竭可能是主要发生在组织特异性T细胞的一种功能失调状态。该发现进一步完善我们对肿瘤情况下T细胞功能失调的科学认知从而促进对现有肿瘤T细胞耗竭理论的修订，也有可能为探索更为有效的抗肿瘤免疫治疗措施提供科学依据。