Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China.
Department of Otolaryngology-Head and Neck Surgery, Tianjin First Center Hospital, Nankai District of Tianjin, Institute of Otolaryngology of Tianjin, Key Laboratory of Auditory Speech and Balance Medicine, Key Clinical Discipline of Tianjin (Otolaryngology), Otolaryngology Clinical Quality Control Centre, Tianjin, People's Republic of China.
Endocr Relat Cancer. 2022 Jan 20;29(2):87-98. doi: 10.1530/ERC-21-0153.
Increasing body of recent studies determining the expression of tumor-specific major histocompatibility complex (MHC) class II protein supports its potential role in several malignancies, but little is known in human medullary thyroid cancer (MTC). Here, we report the expression of MHC-II and its clinicopathologic and prognostic relevance in MTC patients. Immunohistochemistry staining revealed a significant reduction in tumor cell-specific MHC-II expression in a higher AJCC stage and its poor prognostic correlation with human MTC development. Further statistical analysis identified the low MHC-II expression as a significant and independent risk factor for MTC recurrence and patient survival. Moreover, in vitro studies showed that the MHC-II expression was remarkably increased by RET inhibitors, which were prescribed to treat advanced MTC. Similarly, inhibitors blocking the MAPK/ERK and AKT/mTOR pathways also augmented MHC-II expression, suggesting their implications in RET-MHC-II signaling axis. Importantly, in vitro assays manifested enhanced peripheral blood leukocytes-mediated cytotoxicity in MTC cells treated with RET inhibitors, which were partially alleviated by HLA knock-down. Together, our study demonstrates that low MHC-II expression levels may serve as a prognostic biomarker for aggressive diseases in MTC patients and indicates that RET activation may promote MTC immune escape through downregulating MHC-II expression.
越来越多的近期研究确定了肿瘤特异性主要组织相容性复合体 (MHC) Ⅱ类蛋白的表达，支持其在几种恶性肿瘤中的潜在作用，但在人类甲状腺髓样癌 (MTC) 中知之甚少。在这里，我们报告了 MHC-II 在 MTC 患者中的表达及其与临床病理和预后的相关性。免疫组织化学染色显示，肿瘤细胞特异性 MHC-II 表达在更高的 AJCC 分期中显著降低，并且与人类 MTC 发展的不良预后相关。进一步的统计分析确定 MHC-II 低表达是 MTC 复发和患者生存的显著独立危险因素。此外，体外研究表明，RET 抑制剂显著增加了 MHC-II 的表达，RET 抑制剂被用于治疗晚期 MTC。同样，阻断 MAPK/ERK 和 AKT/mTOR 通路的抑制剂也增强了 MHC-II 的表达，表明它们在 RET-MHC-II 信号轴中的意义。重要的是，体外实验表明，用 RET 抑制剂处理的 MTC 细胞中，外周血白细胞介导的细胞毒性增强，而 HLA 敲低部分缓解了这种情况。总之，我们的研究表明，低 MHC-II 表达水平可能作为 MTC 患者侵袭性疾病的预后生物标志物，并表明 RET 激活可能通过下调 MHC-II 表达促进 MTC 免疫逃逸。
