作为肿瘤微环境浸润免疫细胞的重要组成部分，肿瘤相关巨噬细胞在肿瘤细胞不同突变信号作用下发生各种功能表型转化，影响肿瘤细胞生物学行为和抗肿瘤免疫反应，参与肿瘤发生发展、复发转移和治疗抵抗。项目申请人前期研究发现，肾癌患者肿瘤组织Notch1信号活化与肿瘤进展和不良预后以及肿瘤浸润杀伤性T细胞增殖和活化抑制显著相关，进一步分析发现肾癌细胞Notch1信号活化可通过促进IL-6分泌，招募并活化肿瘤相关巨噬细胞表达抑制性免疫分子Galectin-9，引起肿瘤浸润杀伤性T细胞增殖和活化下降。本申请项目拟在前期研究发现的基础上，阐述肾癌细胞促癌信号Notch1活化调控肿瘤相关巨噬细胞功能表型转化抑制抗肿瘤免疫反应并介导免疫逃逸的细胞和分子机制，建立肿瘤相关巨噬细胞功能表型变化参与肾癌细胞促癌信号Notch1活化诱导免疫逃逸的分子调控和靶向干预模型，为认识肾癌发生机制、探索新的肿瘤治疗靶点奠定理论基础。

As a significant component of infiltrating immune cells in tumor microenvironment, tumor-associated macrophages could be transformed into various functional phenotypes driven by multiple tumor intrinsic gene mutational signals. These macrophage phenotypes could then affect the biological behavior of tumor cells and the anti-tumor immune responses, thus to promote tumor development, progression and treatment resistance. Our previous work has found that Notch1 activation in renal cell carcinoma tumor tissue correlated significantly with tumor progression and worse prognoses of patients. Notch1 activation could also inhibit the proliferation and activation of tumor infiltrating cytotoxic T cells. Further analyses revealed that tumor cell intrinsic Notch1 activation could facilitate IL-6 secretion to recruit and activate tumor-associated macrophages to express Galectin-9, which then could reduce the proliferation and activation of tumor infiltrating cytotoxic T cells. Based on these preliminary results, the current project proposal is designed to elucidate the cellular and molecular mechanisms of anti-tumor immune responses inhibition and tumor immune evasion induced by intrinsic Notch1 activation modulating tumor-associated macrophages functional phenotypes alterations. Our present project will attempt to build a molecular regulation and intervention model for tumor-associated macrophage functional phenotypes alterations involving in intrinsic tumorigenic Notch1 activation-mediated tumor immune evasion, which will establish the theoretical basis for understanding oncogenesis mechanisms, and discovering novel therapeutic targets for renal cell carcinoma.