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https://doi.org/10.1530/ERC-21-0153 https://erc.bioscientifica.com © 2022 Society for EndocrinologyPrinted in Great Britain Published by Bioscientifica Ltd. 29:2Endocrine-Related Cancer X Ruan, J Yi, L Hu et al. MHC-II expression and survival in MTC 87–98 -21-0153 RESEARCH Reduced MHC class II expression in medullary thyroid cancer identifies patients with poor prognosis Xianhui Ruan1,*, Jiaoyu Yi1,*, Linfei Hu1,*, Jingtai Zhi2, Yu Zeng1, Xiukun Hou1, Jianfeng Huang 3, Pengfei Gu1, Weijing Hao1, Ming Gao 1,4, Yi Pan5, Songfeng Wei1 and Xiangqian Zheng 1 1Department 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 2Department 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 3Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA 4Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin, People’s Republic of China 5Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China Correspondence should be addressed to Y Pan or S Wei or X Zheng: tjphyLP@126.com or successor317@aliyun.com or xzheng05@tmu.edu.cn *(X Ruan, J Yi and L Hu contributed equally to this work) Abstract 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. [ABSTRACT FROM AUTHOR]