高表达BIRC3的Treg细胞促进结直肠癌肝转移的机制研究

肝转移诊断和治疗是影响结直肠癌预后的最重要因素。目前肝转移依然是结直肠癌研究领域的重点与难点，从免疫微环境展开探索是打破该瓶颈的新视角之一。申请人基于前期单细胞测序技术结果，发现肿瘤组织T细胞浸润与肠癌肝转移预后显著相关，进一步研究发现BIRC3高表达的Treg细胞亚群是促进肠癌肝转移的重要新亚型细胞，并在临床标本以及细胞共培养体系中获得验证，相关结果未见报道。机制探索中发现BIRC3高表达的Treg细胞高分泌IL-35，可抑制B细胞的活化，多重免疫荧光检测也发现肝转移患者标本中活化的B细胞显著降低，据此提出假设“BIRC3高表达的Treg细胞通过高分泌IL-35抑制B细胞的激活，促进肠癌肝转移的发生”。本研究拟从临床标本、细胞水平、动物水平进一步深入探讨BIRC3高表达的Treg细胞促进肠癌肝转移的机制，明确其高分泌IL-35的通路及IL-35如何精细调控B细胞发挥免疫抑制的作用。

Liver metastasis is the most important factor affecting the prognosis of colorectal cancer. Currently, it is still the focus and difficulty of colorectal cancer research. Immune microenvironment is a new perspective to explore the problem. The infiltration of T cells in tumor was found significantly related to the prognosis of colorectal cancer liver metastasis based on single-cell sequencing results. Further studies discovered BIRC3 high-expressed Treg a brand-new subtype promoting liver metastasis. This finding was verified by clinical specimens and cell co-culture system, which was never reported. Further exploration found BIRC3 high-expressed Treg highly secreted IL-35 and inhibited B cell activation. Also, the expression of activated B cell was found to be significantly lower by multiplexed immunohistochemistry. Hereby, a hypothesis was proposed: BIRC3 high-expressed Treg highly secretes IL-35 to inhibit B cell activation and therefore promotes colorectal cancer liver metastasis. This study intends to further investigate the mechanism of BIRC3 high-expressed Treg promoting liver metastasis from clinical, cellular and animal level to uncover how BIRC3 high-expressed Treg highly secretes IL-35 and how IL-35 precisely regulates B cell.