肿瘤综合疗法中免疫治疗占据独特的地位，而免疫治疗方法的提出与革新在于对肿瘤免疫调控网络的深入理解，在于新的免疫治疗靶向性细胞和靶标分子的发现。巨噬细胞作为肿瘤微环境的关键性组成细胞，是肿瘤免疫治疗的重要靶标。可塑性和多变性是肿瘤相关巨噬细胞的重要特征，对其起源、征募方法、维持以及分化作用的具体机理我们还知之甚少。这方面的研究是目前肿瘤免疫治疗研究的热点问题。我们在前期基础上，构建巨噬细胞示踪嵌合体小鼠肝癌模型，发现并鉴定出组织定居性巨噬细胞和单核细胞诱导巨噬细胞。本项目拟进一步分析两群细胞在肝癌进展以及化疗前后的变化情况；通过基因组分析等技术初步筛选两群细胞的标志性分子标志和功能分子；设计体内外实验检测两群细胞在肿瘤微环境中发挥作用的差异，从中筛选出能够选择性清除或诱导肿瘤相关巨噬细胞重新分化的免疫治疗新靶点，为进一步应用于临床研究提出新的免疫治疗方法和并筛选出新的药物作用靶标。

It is the vital target for cancer prevention and therapy to monitor the change in the tumor microenvironment, being essential for tumor cell growth, progression, and development of life threatening metastasis. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. And the clinical challenge remains to block macrophage trophic phenotypes together with their immunosuppressive behaviors and enhance their activation and antitumoral activities. The important characteristics of tumor-associated macrophages are plasticity and variability. The origins of macrophages and their methods of recruitment, retention, and differentiation is not clear. Recent studies suggest that tissue resident macrophages are generated from the embryonic yolk sac and fetal liver under the steady state and a part of tissue macrophages are derived from circulating monocytes in inflammation and cancer. It is the hot topics in study of immunotherapy of cancer to discover the different roles played by tissue resident macrophages and monocytes derived macrophages in tumor microenvironment and the different regulators in the differentiation of these two cell populations and so on. We have been established technology platforms to study the function of myeloid cell subsets in vitro and in vivo, together with establishing hepatocellular carcinoma model. This project aims to find the different function and different cellular and molecular immune regulatory network of tissue-resident macrophages and monocytes derived macrophages in hepatocellular carcinoma. We have found the different distributions of tissue-resident macrophages and monocytes derived macrophages in the development of hepatocellular carcinoma or pre and post chemotherapy with sublethal irradiation and bone marrow transplant. To discover the biomarkers, crucial regulator and transcription factors of these two cell subsets, we will perform genomic analysis and protein chip technology with hepatocellular carcinoma mice model. And we will focus on the study of different roles played by tissue-resident macrophages and monocytes derived macrophages in immune tolerance and tumor metastasis and the underlying molecular mechanisms through in vitro and in vivo experiments. The accomplishment of proposal will provide the novel cellular mechanism underlying the liver cancer and the new key molecules as potential drug targets.