CD19+巨噬细胞诱导免疫抑制微环境促肝细胞肝癌进展机制和干预策略研究

肿瘤相关巨噬细胞（TAM）在肝细胞肝癌（HCC）微环境重塑和免疫治疗抵抗中发挥重要作用，但其表型和功能各异。申请人前期发现HCC中特异性富集CD19+巨噬细胞/TAM，且与HCC局部免疫抑制状态和患者不良预后显著相关，但其来源、细胞特性和促癌机制尚不明确。初步研究发现该群TAM高表达CCR7（趋化因子受体）、Pax5（B细胞发育关键分子）和CD73、PD-1、PD-L1等免疫抑制分子，并上调有氧磷酸化代谢。我们推测：Pax5高表达导致CD19+巨噬细胞/TAM获得超强免疫抑制能力，通过CCR7趋化至HCC，通过CD73介导腺苷途径和PD-1/PD-L1途径诱导免疫抑制微环境，促进HCC进展。本课题拟通过体内外实验和人体标本揭示CD19+巨噬细胞/TAM在HCC中来源、细胞特性和促癌机制，探索靶向联合用药提升免疫治疗效果。本研究将进一步加深对HCC微环境和TAM认识，并有望提出全新治疗策略。

Tumor-associated macrophage (TAM) plays a key role in the reprogramming of microenvironment and resistance of immunotherapy in hepatocellular carcinoma (HCC). However, the phenotype and function of TAM vary a lot. The applicant found a specially enriched CD19+ TAM that is significantly associated with local immunosuppression and poor prognosis in HCC. Unfortunately, the mechanisms of HCC enrichment, cellular feature, and pro-tumor effects of CD19+ TAM are unknown. Our preliminary study revealed that CD19+ TAM overexpresses CCR7 (a chemokine receptor), Pax5 (a B cell developing determinant), and immunosuppressive molecules including CD73, PD-1 and PD-L1. CD19+ TAM also up-regulated activity of oxidative phosphorylation. We thus infer that Pax5 overexpression causes the super-powerfully immunosuppressive activity of CD19+ TAM, which is recruited to HCC through CCR7, and induces immunosuppressive tumor microenvironment by CD73-mediated adenosine and PD-1/PD-L1-mediated immune check point pathways. In this project, we will use in vitro/ in vivo experiments and human sample anslysis to uncover the underlying mechanisms of induction, recruitment, and functions of CD19+ TAM. We will also explore CD19+ TAM-targeted strategy to sensitize immunotherapy in HCC. This project will deepen the understanding of HCC microenvironment and TAM. Additionally, it may lead to emerging of novel treatment strategy and technique.