人新型大肠癌浸润CD39+γδTregs与肿瘤细胞的交互作用及机制研究

Colorectal cancer microenvironment is closely linked to its development and progression. Inflammatory immune cells are one of the major constitutes in the colorectal cancer to promote tumor immune evasion. Our previous study found that γδT17 cells indirectly participate in the formation of immune suppression microenvironment through MDSC recruitment. More than 40% of γδT17 cells also express CD39. Human CD39+γδT cells have more potent immunosuppressive activity than conventional CD4+ regulatory T cells, thus named a novel CD39+γδTregs. In addition, these cells use adenosine to generate an immunosuppressive tumor microenvironment and can be regulated by tumor cell-derived TGF-β1. So we put forward scientific hypothesis “tumor cell-derived TGF-β1-CD39+γδTregs-immune suppression microenvironment”. Based on these findings, we aim to investigate the characteristics, function, and polarization of CD39+γδTregs in the colorectal cancer microenvironment by using human colorectal cancer tissues. Furthermore, we will uncover the underlying mechanism of immune inhibition ability of human CD39+γδTregs through adenosine in colorectal cancers. Then, we will elucidate the cross-talk relationship between CD39+γδTregs and cancer (stem) cells and evaluate its potential value by targeting CD39+γδTregs. These studies will elucidate the roles and mechanisms of novel γδT cell subsets in colorectal cancer and may help identify novel targets for effective immunotherapy for human colorectal cancer.

大肠癌发生发展与肿瘤微环境密切相关，免疫细胞是肿瘤微环境的关键组成。课题组前期发现人γδT17细胞可通过募集MDSC间接参与免疫抑制微环境形成，而40%以上的γδT17细胞表达CD39，新型CD39+γδT细胞在人大肠癌组织明显增高，通过腺苷起到直接免疫抑制功能，其作用较CD4+Treg细胞更强，受肿瘤细胞分泌的TGF-β1调控。因此，课题提出“肿瘤细胞-TGF-β1-CD39+γδTregs-免疫抑制微环境”的学术假说，拟采用流式细胞分选等技术，系统探索人大肠癌组织浸润CD39+γδTregs的功能及临床生物学特征；明确人CD39+γδTregs在大肠癌微环境中地位及腺苷通路在免疫抑制中的作用；阐明肿瘤（干）细胞与CD39+γδTregs的交互作用及其机制；评价靶向干预CD39+γδTregs对预防与治疗大肠癌的潜在应用价值，为靶向干预微环境中关键细胞（分子）进而防治大肠癌提供新的思路。

肿瘤微环境重塑与肿瘤发生发展密切相关。在本项目的资助下，我们完成了可影响肿瘤进展的新型免疫细胞鉴定及其重塑肿瘤微环境机制的探索；在此基础上，拓展研究至微环境中多维度环境调控因子如肠道微生物、缺氧等与不同免疫细胞构成的调控机制网络，全面剖析微环境重塑在肿瘤发生发展中的作用。其中主要的成果有：1.首次证明在人结直肠癌中，新型肿瘤浸润CD39+γδTreg细胞是占主导地位且具有强免疫抑制功能的抑制性T细胞，揭示“肿瘤细胞-TGF-β1-CD39+γδTreg细胞极化-腺苷-免疫抑制微环境-肿瘤进展”肿瘤调控新机制。2.在炎性驱动大肠癌中，将肠道菌群变化与免疫细胞调控相关联，从小鼠模型与人体样本两个维度阐明了肠道菌群产物-单核细胞样巨噬细胞-结肠癌发生的全新机制。3.深入研究了肿瘤微环境对中性粒细胞的影响：在缺氧诱导下，原发灶肿瘤分泌的HMGB1促使中性粒细胞向CD62Ldim方向极化，而具有强粘附力的CD62Ldim 中性粒细胞进一步促进了转移前微环境的形成。以上工作在Gut，Oncoimmunology，Oncogenesis等期刊上发表了论文。通过本项目的研究，揭示了多因素、多成分协同诱导的微环境重塑在肿瘤发生发展的作用，为开展基于微环境的靶向治疗提供新策略。