靶向阻断肿瘤微环境CD45RA-FOXP3hiTreg介导的免疫逃逸抑制头颈鳞癌的作用及机制研究

Regulatory T cells (Treg) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. However, recent study showed that human Treg can be dissected into three functionally distinct subsets. We previously reported that within these Treg subsets, only activated CD45RA-FOXP3hiTreg (aTreg) are significantly related to HNSCC development. Our recent pre experimental results showed that tumor microenvironment Treg exhibit an aTreg phenotype, suggesting that aTreg in tumor microenvironment play an important role in immune escape of HNSCC; meanwhile, aTreg from peripheral blood of HNSCC patients specifically expressed chemokine receptor CCR4. We hypothesized that HNSCC aTreg are recruited into tumor microenvironment with the help of CCR4, and then promote tumor progression by inhibiting host antitumor immune response. Based on our previous studies, this study will further clarify the key role of CCR4 in HNSCC aTreg recruitment; investigate the effect of aTreg on the immune suppression of tumor specific T cells; confirm that blockade of tumor infiltrating aTreg via CCR4 targeting can effectively inhibit HNSCC progression in vitro. This study will provide reasonable evidence for aTreg-targeting immunotherapy of HNSCC.

调节性T细胞（Treg）可通过抑制宿主抗肿瘤免疫反应促进肿瘤的进展，然而近年研究显示Treg存在三类独立的功能异质性亚群。我们前期研究报道：Treg亚群中，仅活化型CD45RA-FOXP3hiTreg（aTreg）与头颈鳞癌的进展密切相关。近期预实验结果显示头颈鳞癌肿瘤微环境中的Treg以aTreg表型为主，提示肿瘤微环境aTreg介导了头颈鳞癌免疫逃逸；同时，我们发现头颈鳞癌患者外周血aTreg特异性表达趋化因子受体CCR4。推测：头颈鳞癌aTreg在CCR4辅助下募集至肿瘤微环境，进而通过抑制宿主抗肿瘤免疫反应促进肿瘤进展。本研究将在前期研究基础上，进一步明确CCR4对头颈鳞癌aTreg的关键趋化作用；探讨aTreg对肿瘤特异性T细胞的免疫抑制作用；体内实验验证以CCR4为靶点阻断aTreg肿瘤微环境浸润可有效抑制肿瘤进展。本课题将为以aTreg为靶点的头颈鳞癌免疫治疗提供合理的依据

本项目围绕目前肿瘤免疫治疗热点问题，针对重要免疫负调控因子调节性T细胞（Treg）展开深入研究，获得重要研究数据，产出科研成果具有重要的科学意义和一定的应用前景，本项目具备一定的创新性，达到了国际同行的认可和好评。本项目首先证实了CCR4 对活化型Treg的关键趋化作用，CCR4 拮抗剂对HNSCC 移植瘤小鼠的肿瘤生长具有抑制作用。此外，头颈部鳞癌肿瘤微环境中存在活化型Treg与肿瘤相关巨噬细胞正反馈环；体内实验证实同时靶向活化型Treg和肿瘤相关巨噬细胞较单独靶向某一类细胞在抑制肿瘤生长的能力上具有明显的优势；最后，头颈部鳞癌肿瘤微环境间质中免疫组化证实头颈鳞癌组织切片中IL-33与Treg分布呈正相关。此外，IL-33可诱导T细胞向Treg分化：CD4+T细胞中加入IL-33和其特异性受体ST2中和抗体，证实IL-33既可诱导IL-10和TGF-b，同时可诱导Treg分化。