口腔鳞癌CD155激活TIGIT通路塑造微环境Tregs表型及功能的作用机制

Phenotype and functional remodeling contribute to the highly proliferative and immunosuppressive of Tregs in the tumor microenvironment. However, the mechanism by which the tumor microenvironment shapes Tregs are still unclear. In the tumor microenvironment, elevated expression of immune checkpoints not only negatively regulate anti-tumor immunity, but also participate in maintaining Tregs, suggesting that activation of immune checkpoints is a possible way to shape Tregs. We previously found that the expression of TIGIT on Tregs was up-regulated in oral squamous cell carcinoma (OSCC) microenvironment, which was closely related to the expression of its ligand molecule CD155 on tumor cells. Moreover, CD155 recombinant protein also enhanced the proliferative and immunosuupressive ability of Tregs. In conjunction with other findings, We proposed that CD155 activates the TIGIT pathway to shape the phenotype and function of microenvironment Tregs, promoting OSCC immune escape. This project aims to explore the remodeling function and mechanism of CD155/TIGIT pathway in Tregs by using OSCC microenvironment staining, in vitro induced Tregs, cell co-culture and humanized mouse tumor models from the following aspects: gene transcription, protein expression, cytokine secretion and cell-cell interaction. This project might provide experimental and theoretical basis for immunotherapy of OSCC.

肿瘤微环境中Tregs能通过表型和功能重塑，获得高度增殖和免疫抑制能力。然而微环境塑造Tregs的途径和机制尚未明确。免疫检查点在肿瘤微环境中异常上调不仅负向调控抗肿瘤免疫，而且参与维持Tregs稳定性和免疫抑制能力，提示激活免疫检查点是塑造Tregs的可能途径。申请人前期发现口腔鳞癌Tregs免疫检查点TIGIT表达上调，与肿瘤细胞表面配体CD155表达密切相关；此外，CD155增强Tregs的增殖和免疫抑制能力依赖于TIGIT的表达。由此提出：口腔鳞癌通过CD155激活TIGIT通路塑造微环境Tregs的表型和功能，促进肿瘤免疫逃逸。本项目拟通过口腔鳞癌微环境染色分析、体外诱导Tregs、细胞共培养和人源化小鼠肿瘤模型，在基因转录、蛋白表达、细胞因子分泌和细胞间相互作用等方面阐明CD155/TIGIT通路对肿瘤微环境Tregs的塑造和分子机制，为口腔鳞癌的免疫治疗提供理论依据。

T细胞免疫球蛋白和ITIM结构域蛋白（TIGIT）是新近发现的抑制性检查点分子，其在口腔鳞癌中的作用尚未清楚。调节性T细胞（Tregs）在肿瘤微环境中能通过表型和功能重塑，获得高度增殖和免疫抑制能力。然而微环境塑造Tregs的途径和机制尚未明确。.本项目发现，与PD-1、CTLA-4、LAG-3和TIM-3等抑制性检查的分子相比，TIGIT在口腔鳞癌患者外周血及肿瘤组织中T细胞上均高表达。高表达TIGIT的T细胞表现为失功能表型。此外，TIGIT在Foxp3+ T细胞上也高表达，并高表达抑制性细胞因子。TIGIT抗体阻断后可逆转T细胞失功能表型，降低Foxp3+ T细胞的抑制能力。上述结果已发表在Oral Diseases，2021，Q1区。在进行此研究的同时，我们发现口腔鳞癌组织中存在CD8+调节性T细胞（Foxp3+ CD8+ T细胞）。进一步分析发现，口腔鳞癌细胞系可通过分泌IL-15、TGF-等细胞因子诱导CD8+ T细胞表达Foxp3分子，变为具有免疫抑制能力的细胞。上述发现有望为口腔鳞癌免疫治疗提供新靶点，以及为口腔鳞癌的发生发展提供新机制。