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Human papillomavirus-encoded circular RNA circE7 promotes immune evasion in head and neck squamous cell carcinoma

Affiliations
  • 1Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2NHC Key Laboratory of Carcinogenesis and Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China.
  • 3Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
  • 4Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5Institute of Biochemistry & Molecular Biology and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
  • 6Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. gongzhaojian4458@csu.edu.cn.
  • 7Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. xiongwei@csu.edu.cn.
  • 8Furong Laboratory, Changsha, Hunan, China. xiongwei@csu.edu.cn.
  • 9Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. zengzhaoyang@csu.edu.cn.
  • 10Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. zengzhaoyang@csu.edu.cn.
  • 11Furong Laboratory, Changsha, Hunan, China. zengzhaoyang@csu.edu.cn.

Published on:

October 4, 2024

Abstract

Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8 T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.

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