LOX-1在巨噬细胞介导的头颈鳞癌免疫逃逸的作用与机制研究

Tumor immunotherapy is currently the fastest growing tumor treatment. Preventing immune escape by regulating immune microenvironment and improving immune response are relevant to tumor immunotherapy (Cell 2017). Our study about tumor infiltrating lymphocytes and T cell receptor was published in Nature Genetics, which found that oxidized low-density lipoprotein receptor LOX-1 is associated with M2 macrophages and vascular growth in head and neck squamous cell carcinoma. Moreover, LOX-1 was overexpressed in the head and neck tumors compared with the normal adjacent tissues as a risk factor for clinical prognosis. The correlation analysis between the receptors of immune checkpoint blockade and LOX-1 illuminates LOX-1 of tumor-associated macrophages (TAMs) is involved in the regulation of microenvironment in head and neck tumors, but its specific mechanism and clinical relevance are still to be elucidated. In this study, we discuss the role of LOX-1 of TAMs in the promotion of head and neck squamous cell carcinoma and explore the molecular mechanism of LOX-1 on tumor microenvironment regulation from three levels: co-culture cell model, xenograft mouse model and LOX-1 knockout mouse model. The relationship between LOX-1 and specific T/BCR and the transcription factor control network associated with LOX-1 are studied. The molecular mechanism of LOX-1-specific immunity was confirmed by TAMs. Finally, the clinical significance of LOX-1 protein expression was verified by our clinical cohort. The results will help to clarify the immune escape mechanism of head and neck cancer, which will provide the new strategy for the prevention and treatment of head and neck squamous cell carcinoma.

肿瘤免疫治疗是目前发展最快的肿瘤治疗方向。通过调控免疫微环境阻断免疫逃逸，提高免疫反应水平是肿瘤免疫治疗的关键(Cell 2017)。申请人在估计肿瘤浸润淋巴细胞含量和组装T细胞受体的研究中(Nature Genetics, 2016，共一)发现，氧化低密度脂蛋白受体LOX-1在头颈鳞癌中与M2型巨噬细胞的浸润水平和促血管生长标志物呈高度正相关，且在头颈肿瘤中高表达，是临床预后的风险因子；结合与免疫检查点受体的相关分析，推测LOX-1在巨噬细胞中参与对头颈肿瘤微环境的调控，但其具体的机制及临床价值亟待深入阐明。本课题拟分别从细胞共培养模型、移植瘤模型、基因敲除鼠模型三个水平明确LOX-1通过巨噬细胞促进头颈鳞癌发生发展的作用，同时通过算法研究LOX-1与特异性免疫之间的关系，探究LOX-1对肿瘤微环境调控的分子机制。成果将有助于阐明头颈肿瘤的免疫逃逸机制，将为头颈鳞癌的防治提供新的思路。

头颈鳞癌严重危害人类健康，基于免疫治疗的肿瘤疗法是近年来发展最快的肿瘤治疗方向，为实现头颈部鳞癌的精准杀伤和改善患者预后提供契机，是受关注的前沿。本项目基于在肿瘤免疫研究的前期工作，分别通过细胞共培养模型和动物模型明确LOX-1通过巨噬细胞促进头颈鳞癌发生发展的作用，同时通过开发算法研究LOX-1与特异性免疫之间的关系，探究LOX-1对肿瘤微环境调控的分子机制。通过实验发现，LOX-1可促进头颈鳞癌的血管生成、EMT以及发生发展；LOX-1参与Casticin药物抑制口腔鳞癌的过程；临床组织的单细胞转录组揭示LOX-1在巨噬细胞中高表达；开发了新的用于研究肿瘤浸润免疫细胞分析工具TIMER2.0，发现LOX-1与肿瘤免疫浸润的紧密互作关系；开发了肿瘤免疫微环境的可视化单细胞数据库TISCH，发现LOX-1在广泛肿瘤的巨噬细胞中高表达。.项目执行期间，发表标注本项目资助的SCI论文3篇，包括国际高水平期刊Nucleic Acid Res (2020, 2篇)，J Oral Pathol Med.(2019)，2篇在投。同时作为负责人获得国家自然科学基金面上项目1项，中国博士后科学基金特别资助(站中) 1项。获2018年中华口腔医学会口腔医学青年科学家论坛“明日之星”奖，2019年IADR中国分会第15届杰出青年学者奖一等奖。.总之，本项目在科学研究和人才培养等方面取得了突出成绩，孵育了新的课题，为头颈鳞癌的防治提供新的靶点，对头颈鳞癌的防治产生了积极影响。

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