肾癌细胞Notch1信号活化分泌IL-6促进肿瘤相关巨噬细胞产生Galectin-9介导免疫逃逸的机制研究

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.

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。

在本项目资助下，项目负责人围绕巨噬细胞生物学方向，深入研究在肿瘤发生过程中异常巨噬细胞功能表型转化的分子机制及其功能意义，并取得一系列研究成果。以通讯作者在Journal for Immunotherapy of Cancer、European Urology、British Journal of Cancer、Cancer Immunology Immunotherapy等肿瘤免疫学领域国际权威期刊上发表5篇SCI论文。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密切相关。Notch1异常活化的肾癌患者常伴有BAP1突变，肾癌细胞Notch1信号活化可促进NF-κB信号的激活和IL-6分泌，招募活化Galectin-9+肿瘤相关巨噬细胞，巨噬细胞中HIF-1α信号活化及其下游的IL-23分泌增加，后者通过刺激肿瘤浸润Treg细胞分化形成CCR5+Treg细胞亚群并分泌TGF-β，进而促进CD8+T细胞向耗竭型PD-1+TIM-3+CD8+T细胞分化，促进肾癌免疫逃逸形成。阻断Notch1信号可抑制肿瘤细胞PD-L1表达并诱导肿瘤相关巨噬细胞向抑癌功能表型转换从而减缓肿瘤进展。本项目阐明了肿瘤相关巨噬细胞功能表型变化参与肾癌细胞促癌信号活化诱导免疫逃逸过程中的作用和细胞与分子机制，这些发现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。