利用同源异型头颈鳞癌小鼠模型研究肿瘤特异性CD8+T细胞的分子特征和功能调控

Tumor-specific CD8+ T cells are the main functional cells in immunotherapy, however, the characteristic markers and functional regulation of this cell group are still unclear. Through 4NQO induction and CRISPR/Cas9-mediated B2m knockout, we obtained two head and neck squamous cell carcinoma mouse models that were from the same cell line (same origin), but had different function of CD8+ T cells in their tumor microenvironments (different immunotypes). Using this set of models, we will investigate the relevant indicators and translational value of tumor-specific CD8+ T cells. First, using single-cell technologies to identify the characteristic markers of tumor-specific CD8+ T cells and its subsets. Then, using in vitro and in vivo tumor-immune system to study the tumor killing ability of tumor-specific CD8+ T cells and its subsets, to summarize their changes in tumor progression and PD-1 blocking therapy, and to search for related regulatory cells. At last, through the study of anti-PD-1 immunotherapy simulation, clinical sample information and humanized PDX, the potential of tumor-specific CD8+ T cell related indicators in the prediction of immune response and the development of new therapeutic targets will be explored. This study will provide further understanding of the interaction between solid tumor and tumor-specific CD8+ T cells, and is expected to identify new predictors and therapeutic targets for tumor immunotherapy.

肿瘤特异性CD8+T细胞是免疫治疗的关键类群，但我们对这群细胞的分子特征和功能调控尚缺乏认识。通过4NQO诱导和B2m敲除，得到来自同一细胞系（同源）但肿瘤中CD8+T细胞的分布与功能不同（免疫类型不同）的头颈鳞癌小鼠模型组合。我们将利用该组模型研究肿瘤特异性CD8+T细胞的相关指标和转化价值。首先，利用多种单细胞分析技术来鉴定肿瘤特异性CD8+T细胞/亚群的特征标志物。然后，利用体内、外的肿瘤免疫体系研究肿瘤特异性CD8+T细胞/亚群的杀伤功能，总结它们在肿瘤进展及PD-1阻断治疗中的变化规律，并寻找相关的调控细胞。最后，通过对抗PD-1免疫治疗模拟、临床样本信息和人源化PDX的研究，探索肿瘤特异性CD8+T细胞相关指标在免疫治疗响应预测和新靶点开发方面的转化潜力。本研究将加深我们对于实体瘤与肿瘤特异性CD8+T细胞相互作用的理解，并有望为肿瘤免疫治疗提供新的预测指标和治疗靶点。

肿瘤特异性CD8+T细胞是免疫治疗的关键类群。通过4NQO诱导和B2m敲除，得到来自同一细胞系（同源）但肿瘤中CD8+T细胞的分布与功能不同（免疫类型不同）的头颈鳞癌小鼠模型组合。利用该组模型研究了肿瘤特异性CD8+T细胞的相关指标和转化价值。首先，我们建立了三株HNSCC细胞系；然后，利用体内、外的肿瘤免疫体系研究用于初步探索了头颈部鳞状细胞癌和淋巴细胞之间的相互作用，并验证新的免疫治疗靶点；最后，利用头颈鳞癌标本、癌症基因组图谱以及小鼠头颈鳞癌模型的研究，对于HPV阴性头颈鳞癌和肿瘤浸润淋巴细胞的共同进化特征进行了初步研究。本研究将加深了我们对于实体瘤与肿瘤特异性CD8+T细胞相互作用的理解，并有望为肿瘤免疫治疗提供新的预测指标和治疗靶点。