ICAM-1+CD51+CAFs调控TAM和MDSCs介导结直肠癌免疫抑制的作用和机制研究

肿瘤相关成纤维细胞（CAFs）是肿瘤微环境中具有异质性的重要间质细胞，与结直肠癌(CRC)的复发和转移密切相关。我们前期发现CRC中存在一群独特表型的CAFs亚群（ICAM-1+CD51+），具有较强募集单核细胞并诱导其分化为M2型TAM和M-MDSCs的能力；还发现微环境中的骨桥蛋白可活化p38 MAPK通路并促进ICAM-1+CD51+CAFs分泌MCP-3、CXCL5和IL-6。我们推测：骨桥蛋白可通过CD51活化p38 MAPK通路，促进ICAM-1+CD51+CAFs分泌MCP-3、CXCL5和IL-6等，造成微环境免疫抑制细胞TAM和MDSCs累积，导致CRC免疫逃逸。本课题拟确定ICAM-1+CD51+CAFs与CRC患者预后的关系，阐明ICAM-1+CD51+CAFs调控TAM和MDSCs诱导CRC免疫抑制微环境形成的作用及机制，为靶向肿瘤微环境的治疗提供新思路和靶点。

Cancer-associated fibroblasts (CAFs) represent a functionally heterogeneous population of activated fibroblasts that constitutes a major component of tumor stroma. Here, we demonstrate that two cell-surface molecules, ICAM-1 and CD51, specifically define a CAF subset correlated with immunosuppression in colorectal cancer. ICAM-1+CD51+CAFs has a strong ability to recruit monocytes and induce them to differentiate into M2 TAM and M-MDSCs. We also found osteopontin can promote the secretion of MCP-3, CXCL5 and IL-6 via regulating the p38 MAPK pathway. We speculate that osteopontin derived from CRC cells and CAFs can bind to CD51, promote the secretion of MCP-3, CXCL5 and IL-6. ICAM-1+CD51+CAFs-derived MCP-3、CXCL5 and IL-6 promoted colorectal cancer progression by modulating the tumour microenvironment towards an immune suppressive milieu and by TAM and MDSC recruitment. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers. We aimed to determine the correlation between ICAM-1+CD51+CAFs and prognosis of CRC patients, and clarify the role and mechanism of ICAM-1+CD51+CAFs in regulating the CRC immunosuppression microenvironment..Our study reveals a functional CAFs subset and suggests that targeting the ICAM-1+CD51+CAFs subset could be a potential therapeutic path to reverse the CAFs-mediated immunosuppressive microenvironment.