p53突变触发IL-34依赖的免疫逃逸驱动肝癌进展

免疫疗法已显示出强大的抗肿瘤活性，但由于肿瘤微环境的高度异质性，其仅对少部分患者有效；进一步了解肿瘤免疫微环境将有助于提高免疫治疗的疗效。肿瘤中的致癌基因突变会通过调节免疫因子来塑造肿瘤免疫微环境，促进肿瘤的免疫逃逸；然而，p53作为肿瘤中最频繁突变的基因，塑造其免疫微环境的关键因子尚不清楚。因此本项目致力于探究p53突变肝癌的免疫逃逸机制，并开发新的免疫治疗方法。我们通过构建不同基因突变的小鼠自发肝癌模型，发现IL-34在p53突变驱动的肝癌显著上调表达，并在其发生发展中起重要作用。后续本项目将证明：p53调控IL-34表达的机制；p53突变肝癌形成以巨噬细胞为主的免疫抑制性微环境；IL-34诱导巨噬细胞极化成M2表型的机制；p53突变肝癌的免疫抑制性微环境由IL-34主导塑造；抗体阻断IL-34有效抑制p53突变肝癌的生长；最终证明IL-34抗体阻断疗法是p53突变肝癌的特异性疗法。

Although immunotherapy has shown strong anti-tumor activity, only a small percentage of patients respond due to the heterogeneity of the tumor microenvironment. Further understanding of the tumor immune microenvironment will help improve the efficacy and response rates of immunotherapy. The carcinogenic mutations can shape the immune microenvironment and promote the immune escape of tumors by regulating immune factors; however, it is unclear that the key factor in shaping immune microenvironment of p53, as the most frequent mutation gene in tumors. Therefore, this project is committed to exploring the immune escape mechanism of p53 mutant liver cancer and developing new immunotherapy. By constructing spontaneous liver cancer models in mice with different mutant gene, we found that IL-34 was significantly up-regulated in liver cancer driven by p53 mutation, and played an important role in its occurrence and development. The follow-up project will prove: (1) the mechanism of p53 regulating IL-34 expression; (2) liver cancer driven by p53 mutation forms an immunosuppressive microenvironment dominated by macrophages; (3) The mechanism of IL-34 drive the polarization of macrophages towards M2 phenotype; (4) The immunosuppressive microenvironment of liver cancer driven by p53 mutation is mainly shaped by IL-34; (5) Antibody blocking IL-34 effectively inhibits the growth of liver cancer driven by p53 mutation; finally illustrate that IL-34 antibody blocking therapy is specific therapy for liver cancer driven by p53 mutation.