RIP3调控髓系来源抑制性细胞趋化募集促进肝癌免疫逃逸的机制研究

How to inhibit tumor immune escape and improve antitumor efficacy is currently the focus and difficulty of cancer immunotherapy. In recent years, it becomes clear that the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment plays an important role in tumor immune escape. However, the mechanisms of MDSCs recruitment into the TME remain unclear. Our previous studies demonstrated that the abundance of MDSCs in HCC tissues was significantly higher than matched adjacent liver tissues. Concordant overexpression of RIP3 and MDSCs markers was observed in HCC patients. Furthermore, the chemotaxis assay proved that knockdown of RIP3 in hepatoma cells could effectively inhibit MDSCs recruitment. Based on discoveries above, we aim to clarify the exact mechanisms of MDSCs recruitment by utilization of plenty clinical samples and various animal and cell modes. We mainly focus on three controversies: 1) The role of RIP3 in MDSC recruitment by clinical samples and function assays, and the clinical significance for progression and prognosis of HCC. 2) The key chemokine-receptor axis regulated by RIP3 in MDSCs recruitment, elucidate the molecular mechanisms of MDSC recruitment regulated by RIP3 in HCC immune escape. 3) Conduct the study of RIP3 inhibitor in HCC immunotherapy. In conclusion, accomplishment of this research program will be of great significance in discovering novel immunotherapy targets, developing immunotherapy drugs and improving antitumor efficacy of HCC immunotherapy.

如何抑制肿瘤免疫逃逸从而提高免疫治疗的疗效是目前临床肿瘤免疫治疗的重点和难点。近年来大量研究表明肿瘤微环境中髓系来源抑制性细胞（MDSCs）的趋化募集是肿瘤免疫逃逸的重要原因。但是MDSCs趋化募集的调控机制尚不清楚。我们前期的研究发现，人肝癌组织中MDSCs的浸润数量显著增加，RIP3的表达水平与MDSCs的浸润数量呈正相关。干涉RIP3可以降低MDSCs在肝癌组织的趋化募集。本项目在前期研究基础上，运用大量临床标本和多种动物模型、细胞模型，深入探讨: 1)RIP3介导MDSCs趋化募集的作用及对肝癌进展和预后的临床意义。2)RIP3调控MDSCs趋化募集的关键趋化因子和受体，阐明RIP3调控MDSCs趋化募集促进肝癌免疫逃逸的机制。3)开展RIP3抑制剂联合趋化因子抗体抗肝癌免疫治疗的研究。该课题的完成将对寻找肝癌免疫治疗新靶点，研发肝癌免疫治疗药物，提高肿瘤免疫治疗疗效具有重要意义。

肿瘤免疫治疗已成为肿瘤治疗领域中最具前景的研究方向和最具潜力的治疗手段。如何提高肿瘤免疫治疗疗效，扩大受益人群，是目前肿瘤免疫治疗临床研究的重点和难点。肿瘤免疫逃逸是肿瘤免疫治疗失败的主要原因。免疫逃逸是指肿瘤细胞在肿瘤微环境中通过多种机制突破免疫系统监控，逃避免疫系统识别与杀伤，进而继续增殖、侵袭和转移的现象。肿瘤免疫逃逸是一个复杂的、多因素、多步骤共同调控的综合病变过程，分子机制复杂。MDSCs 是一类具有强大免疫抑制功能的免疫调节细胞，通过抑制效应 T 细胞和自然杀伤细胞等抗肿瘤免疫细胞的效应功能介导肿瘤免疫逃逸。因此，寻找调控 MDSCs 趋化募集的关键趋化因子，对于抑制肿瘤免疫逃逸、增强肿瘤免疫治疗效果具有十分重要的意义。在本课题的研究中，我们发现肝癌组织中RIP3分子表达水平显著降低，RIP3分子可以作为肝癌患者预后的重要指标。进一步研究发现RIP3与MDSCs在肿瘤微环境的聚集密切相关。干涉RIP3分子可以增加MDSCs在肝癌组织的浸润水平，降低IFN-γ+CD8+T细胞的浸润丰度，进而促进肝癌免疫逃逸和肝癌进展。RIP3敲除后，通过磷酸化P65(SER536)以及促进P65(SER536)核转位，促进其与CXCL1启动子结合，进而增加CXCL1的转录，促进CXCL1的表达，从而募集CXCL1的受体分子CXCR2表达阳性的MDSCs。CXCR2拮抗剂可以抑制RIP3敲除小鼠肝脏MDSCs的趋化募集和肝癌进展。结论：RIP3是促进MDSCs向肝脏组织趋化的关键分子，可以通过CXCL1-CXCR2趋化轴募集MDSCs促进肝癌免疫逃逸和肝癌进展。阻断CXCL1-CXCR2趋化轴有望为抑制肝癌免疫逃逸提供新策略。.