淋巴结转移灶中胆管癌通过PPARγ脂质代谢重编程诱导T细胞耗竭的机制研究

易发淋巴结转移是胆管癌的重要特征及不良预后因素。研究表明肿瘤细胞在转移灶会发生显著代谢重编程以适应新的微环境，但胆管癌如何适应及影响淋巴结微环境尚不明确。我们前期发现胆管癌淋巴结转移灶免疫抑制程度高，并利用单细胞测序发现其中的胆管癌细胞发生了转录因子PPARγ（过氧化物酶体增殖体激活受体γ）调控的脂质代谢重编程。初步机制研究显示，淋巴液可诱导胆管癌细胞激活PPARγ，上调FABP1、CPT1A表达以促进脂质摄入及氧化，其肿瘤上清可促T细胞耗竭。据此我们提出假说：胆管癌细胞上调PPARγ调控的脂质代谢重编程以适应淋巴结微环境，并分泌脂质代谢物促T细胞耗竭实现免疫逃逸。本项目拟结合临床标本和体内外实验进一步阐明PPARγ对胆管癌脂质代谢的调控及促T细胞耗竭的分子机制。本项目将明确胆管癌如何通过PPARγ适应并影响淋巴结微环境、为确立PPARγ作为胆管癌患者治疗的新靶点提供科学依据。

Lymph node metastasis is an important feature and poor prognostic factor for cholangiocarcinoma. Researches have shown that tumor cells undergo significant metabolic reprogramming in metastases to adapt to the new microenvironment, but how cholangiocarcinoma adapts to and affects the lymph node microenvironment remains unclear. We previously found that cholangiocarcinoma lymph node metastases were under immune-suppressive conditions, while single-cell sequencing showed that cholangiocarcinoma cells in lymph node metastases underwent lipid metabolism reprogramming regulated by the transcription factor PPARγ (Peroxisome Proliferator Activated Receptor Gamma). Preliminary mechanism studies showed that lymph fluid could induce cholangiocarcinoma cells to activate PPARγ, up-regulating FABP1 and CPT1A to promote lipid uptake and oxidation, while the tumor supernatant could induce T cell exhaustion. In view of the above, we hypothesize that cholangiocarcinoma cells up-regulate PPARγ-regulated lipid metabolism reprogramming to adapt to the lymph node microenvironment, and secrete lipid metabolites to induce T cell exhaustion and then immune escape. This project aims to clarify the in-depth molecular mechanism of cholangiocarcinoma lipid metabolism reprogramming and induction of T cell exhaustion regulated by PPARγ through in vitro intervention, animal models and clinical specimens. The results promise to elucidate how cholangiocarcinoma adapts to and affects lymph node microenvironment, providing evidence for targeting PPARγ as a new therapeutic strategy for cholangiocarcinoma patients.