线粒体动力相关蛋白DRP-1调控舌鳞癌细胞MHC-Ⅰ表达及免疫原性的机制研究

The hypoexpression of MHC-Ⅰ on tumor cell membrane leads to low immunogenicity and immune escape to a great extent. Basing on our previous researches, mitochondrial dynamics is associated with biological behavior and prognosis of tongue squamous cell carcinoma(TSCC), but the correlation between mitochondrial dynamics and tumor immunogenicity has never been reported. We initially demonstrated that inhibition of mitochondrial fission could restore the expression of MHC-Ⅰ on TSCC cell membrane by preliminary experiments. Meanwhile, we discovered that mitochondrial dynamics is associated with endoplasmic reticulum stress(ER Stress) while ER Stress and the expression of MHC-Ⅰ are of negative correlation. Therefore we established the model of inhibition of mitochondrial fission to inhibit ER Stress in order to ultimately reconstruct the immunogenicity of TSCC for the first time. We will explore the molecular mechanism of how ER Stress regulates the immunogenicity of TSCC by autoradiography experiments, Endo H assay in subsequent research. The feasibility of aforementioned model and its relationship with prognosis will be further verified by clinical sample analysis and in vivo experiments. This research takes mitochondrial dynamics as a starting point, exploring the regulation mechanism of tumor immunogenicity in depth, will provide new directions and targets for tumor therapy.

肿瘤细胞表面MHC-Ⅰ分子表达降低是其免疫原性降低、发生免疫逃逸的重要原因之一。申请人既往在线粒体动力学方面的研究已阐明线粒体动力学与舌鳞癌生物学行为及患者预后相关，但是否影响其免疫原性尚未见报道。我们通过预实验初步证实抑制线粒体分裂可恢复舌鳞癌细胞表面MHC-Ⅰ分子的表达，同时还发现线粒体动力学与内质网应激(ER Stress)存在相关性，且ER Stress强度与MHC-Ⅰ的表达呈负相关，由此首次建立起抑制线粒体分裂进而抑制ER Stress并最终重建舌鳞癌细胞免疫原性的模型。后续研究我们将通过放射自显影、Endo H assay等技术明确ER Stress调控舌鳞癌免疫原性的分子机制，并通过体内实验及临床样本分析验证线粒体分裂调控舌鳞癌细胞免疫原性的可行性及与预后的相关性。该课题以线粒体分裂作为切入点，深入探讨其对肿瘤免疫原性的分子调控机制，将为肿瘤免疫治疗提供新的方向和靶点。

肿瘤细胞表面MHC-Ⅰ分子表达降低是其免疫原性降低、发生免疫逃逸的重要原因之一。我们通过抑制肿瘤线粒体分裂，发现线粒体动力学可调控患者及小鼠肿瘤细胞表面 MHC-Ⅰ 分子的表达，机制研究中发现ER Stress UPR 信号通路中的IRE1α-XBP-1s轴在线粒体分裂与免疫原性联系中起关键作用，XBP-1s作为氨基肽酶TPP2的转录因子，通过降解肿瘤抗原多肽来抑制肿瘤细胞表面 MHC-Ⅰ 分子的表达。通过体内实验及临床样本分析证实了线粒体分裂调控舌鳞癌细胞免疫原性的可行性及与预后的相关性。该课题以线粒体分裂作为切入点，深入探讨其对肿瘤免疫原性的分子调控机制，研究成果发表在《Nature Communications》，将为肿瘤免疫治疗提供新的方向和靶点。