CD19+CD5+CD1dhi调节性B细胞在炎症相关结肠癌免疫逃逸中的作用机制研究

Chronic inflammation is linked to the development of colon cancer, and tumor escape from immune surveillance is an important factor of inflammatory-cancer transformation. Regulatory B cells (Breg) play an immunosuppressive function by secreting IL-10 and interacting with immune cells, but the regulatory function of Breg cells has changed under the sustained stimulation of inflammatory signals. It is not clear whether the microenvironment of colitis-associated colon cancer can change the regulatory phenotype of Breg cells, which promote tumor escape from immune surveillance in the other cancer. Previous studies found that the number of CD19+CD5+CD1dhi Breg cells, the expression of IL-10 and the level of STAT3 phosphorylation in CD19+CD5+CD1dhi Breg cells were reduced in the tumor tissue of colon cancer after inflammatory-cancer transformation. These data suggest that the phenotype of Breg cells has been changed. Based on our previous study, we plan to prepare the models of colitis and colitis-associated colon cancer, study the interaction between Breg cells and immune cells in colitis and colitis-associated colon cancer, analyze the signaling pathways that control the function of Breg cells, explore the prevention and treatment of colitis-associated colon cancer by Breg cells, address the role of Breg cells in immune escape mechanisms of colitis-associated colon cancer. Finally, we hope to provide new ideas for the clinical treatment of colitis-associated colon cancer.

慢性结肠炎可导致结肠癌的发生，肿瘤细胞的免疫逃逸是炎-癌发生转化的重要原因。调节性B细胞（Breg）通过分泌IL-10以及与免疫细胞间相互作用发挥免疫抑制功能，但在炎性信号持续刺激下其功能表型也可发生变化。在炎症相关的结肠癌中Breg细胞表型是否发生变化且参与肿瘤免疫逃逸的机制不明。前期研究发现，结肠炎转化为结肠癌后，肿瘤组织内CD19+CD5+CD1dhiBrg细胞数量减少，分泌IL-10能力降低，胞内STAT3磷酸化水下降，提示Breg细胞在炎症相关结肠癌中表型发生了改变，并参与了肿瘤的免疫逃逸。本课题结合前期研究，制备结肠炎和炎症相关结肠癌模型，通过研究炎症和肿瘤中的Breg细胞与免疫细胞之间的相互作用，分析调控Breg细胞功能发生变化的信号通路，探索Breg细胞对炎症相关结肠癌的预防和治疗，阐明Breg细胞参与炎症相关结肠癌免疫逃逸的机制，为结肠癌的防治开辟新的免疫疗法奠定基础。

结直肠癌发生的一个重要原因是肠道内炎症信号的长期刺激。肠道内CD19+CD5+CD1dhi调节性B细胞（Breg 细胞）通过分泌细胞因子IL-10以及与免疫细胞相互作用发挥免疫抑制功能，抑制炎症应答的强度，阻止炎症向癌症转化。但在炎性信号持续刺激下，Breg 细胞功能表型可发生变化。本课题研究了Breg细胞在结肠炎和炎症相关结肠癌中的功能变化，发现Breg细胞分泌细胞因子IL-10以及抑制T细胞应答的功能在炎症诱导的结肠癌中显著下降。探索了Breg细胞表型发生变化与炎症之间的关系，并且阐明了这种变化与STAT3信号通路之间的联系，同时也发现了调控B细胞应答的其他重要分子。另外我们也建立了Breg细胞体外大量扩增的方法，为使用调节性B细胞，抑制炎症应答，治疗炎症模型提供了基础。