自噬促进NLRC5介导的MHCⅠ抗原提呈在子宫内膜癌免疫逃逸中的作用

The chemoradiotherapy effect of endometrial cancer is poor. Immunotherapy brings hope for the endometrial cancer treatment. However, Tumor immune escape is a hot potato in clinical tumor immunotherapy. It was indicated that tumor cell could go through immune escape by inhibiting NLRC5 mediated MHCⅠantigen presentation. Studies have also suggested that autophagy can promote MHCⅠmediated antigen presentation which further damages tumor cell. But whether autophagy plays a role in NLRC5 mediated MHCⅠantigen presentation in endometrial cancer is unclear yet. Our preliminary experiment found that the levels of NLRC5 in endometrial cancer patients were down-regulated compared with normal endometrium tissue. Furthermore, NLRC5 and LC3 were co-localized in cytoplasm, promoting autophagy contributes to the expression of NLRC5, which indicated that autophagy seems plays a role in NLRC5 mediated MHCⅠantigen presentation in endometrial cancer. In our study, we first change the levels of autophagy in endometrial cancer cell and detect the levels of MHCⅠantigen presentation and NLRC5, we also interfere NLRC5 to investigate whether autophagy promotes MHCⅠmediated antigen presentation by regulating NLRC5 which was further comfirmed in nude mice of subcutaneous xenotransplanted tumor model. Last, we collect pathological specimen of endometrial cancer patients and normal endometrium tissue specimens and analyse the correlation between autophagy related proteins and NLRC5. The study provides evidence for the immunotherapy in endometrial cancer.

子宫内膜癌的放化疗效果差，免疫治疗带来了曙光，但肿瘤的免疫逃逸成为治疗障碍。研究证实肿瘤细胞会抑制NLRC5介导的MHCⅠ抗原提呈发挥免疫逃逸。亦有研究表明自噬会促进MHCⅠ抗原提呈损伤肿瘤细胞，但子宫内膜癌中自噬是否调控NLRC5介导的MHCⅠ抗原提呈尚不清楚。我们前期发现NLRC5在子宫内膜癌患者中较正常子宫内膜组织低表达，子宫内膜癌细胞中LC3与NLRC5共定位于细胞浆，促进自噬会促进NLRC5的表达，提示自噬可能调控NLRC5介导的MHCⅠ抗原提呈。为了验证这一假说，我们拟首先在子宫内膜癌细胞上调整自噬的水平，检测MHCⅠ途径抗原提呈和NLRC5，干预NLRC5，探索自噬是否调控NLRC5介导的MHCⅠ途径抗原提呈；并在裸鼠皮下移植瘤模型中验证；最后在临床上收集子宫内膜癌患者以及正常的子宫内膜标本，分析自噬相关蛋白与NLRC5表达相关性，为子宫内膜癌的免疫治疗提供依据。

主要组织相容性复合体I类(MHC-I)转录激活因子，核苷酸结合寡聚域样受体家族caspase招募域5 (NLRC5)，在包括子宫内膜癌在内的许多癌症中作为重要的免疫逃避的靶点之一。研究已证实抑制自噬可以通过协助促进MHC-I介导的抗原呈递来促进肿瘤的免疫治疗。然而，自噬调节MHC-I在子宫内膜癌中的潜在机制尚不清楚。在本研究中，我们旨在探索子宫内膜癌中自噬调节MHC-I的机制。临床标本中我们发现与正常子宫内膜组织相比，子宫内膜癌组织中的自噬水平上调。子宫内膜癌组织中MHC I和NLRC5的表达低于正常子宫内膜。体外细胞实验发现自噬可以抑制MHC-I相关基因的表达。此外，NLRC5和LC3水平呈负相关，体外细胞实验和体内动物成瘤实验发现LC3可以与NLRC5相互作用进而抑制NLRC5介导的MHC-I抗原递呈途径。因此，我们的研究结果表明，在子宫内膜癌患者中，LC3的上调可能通过限制NLRC5介导的MHC-I抗原递呈途径，促进肿瘤免疫逃逸，表明在子宫内膜癌中，抑制LC3和促进NLRC5可能是一种有前途的免疫治疗策略。