TIM1+Breg细胞经Treg/CTL细胞途径促进肝癌免疫逃逸的机制研究

Regulatory B (Breg) cells are closely related to tumor immune escape and have heterogeneity. To clarify the phenotypic characteristics and mechanism of Breg cells in hepatocellular carcinoma (HCC) can help to better understand the immune escape of HCC..Our previous study has found that T-cell immunoglobulin (TIM) 1+ B cells have Breg cell characteristics, and accumulate in tumor tissues of HCC, especially advanced patients, suggesting that TIM1+ Breg cells play an important role in the invasion of HCC. In addition, TIM1+ Breg cells directly affect the proportion of regulatory T (Treg) cells and cytotoxic T (CTL) cells, suggesting that the change in above cell subsets could be one key mechanism of TIM1+ Breg cells in promoting HCC immune escape. Thus, we propose that TIM1+ Breg cells may promote HCC immune escape by affecting Treg/CTL cells..This study will identify the role of TIM1+ Breg cells in the progression of HCC and the effects of TIM1+ Breg cells on the Treg/CTL cells, and reveal the new molecules and the new mechanism involved in the effects of TIM1+ Breg cells on Treg/CTL cells. This study helps to provide the evidences for HCC immunophenotype staging and new immunotherapy strategy based on TIM1+ Breg cells.

调节性B（Breg）细胞与肿瘤免疫逃逸密切相关，且异质性较大，明确肝癌中Breg细胞的特点及作用机制有助于更透彻理解肝癌的免疫逃逸。我们前期研究发现TIM1+B细胞具有Breg细胞特性，在肝癌病人，尤其在晚期病人癌组织聚集，提示TIM1+Breg细胞在肝癌侵袭中起着重要作用；此外，TIM1+Breg细胞直接影响调节性T（Treg）细胞和细胞毒性T（CTL）细胞比例，提示诱导上述细胞亚群的变化是TIM1+Breg细胞促进肝癌免疫逃逸的关键。据此我们提出假说：TIM1+Breg细胞可能是通过影响Treg/CTL细胞来促进肝癌免疫逃逸。本课题拟利用体内外模型明确TIM1+Breg细胞在肝癌进展中的作用，及其对Treg/CTL细胞的影响，揭示TIM1+Breg细胞影响Treg/CTL细胞的新分子与新机制。本研究为研制以TIM1+Breg细胞为靶标的肝癌免疫分型标准和新型免疫治疗手段提供理论基础。

本项目系统研究了TIM1+Breg细胞在肝癌进展中的作用及其机制，发现TIM1+Breg细胞与肝癌分期呈正相关，与肝癌预后呈负相关。功能研究发现TIM1+Breg细胞表达IL-10，能够抑制CD8+T细胞的功能，而髓系细胞通过TIM4/TIM1信号促进TIM1+Breg细胞表达IL-10。机制研究发现肿瘤外泌体通过HMGB1诱导B细胞表达TIM1，进而抑制CD8+T细胞的功能；HMGB1主要通过激活MAPK通路诱导TIM1+Breg细胞生成。本项目阐明了TIM1+Breg细胞在肝癌免疫逃逸中的作用，并揭示了肝癌免疫逃逸的新机制，不仅有利于我们更全面的理解肝癌免疫逃逸的机理，也为研制以TIM1+Breg细胞为靶标的肿瘤分子分期标准和新型防治手段提供理论基础。