1. Department of Gynecology and Obstetrics, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong, 518036, China.
3. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
Although m6A modifications are associated with tumor progression, and anti-tumor immune responses, the role of m6A regulators in HPV-related carcinogenesis has not been well resolved. To provide evidence for the role of m6A regulators in HPV-related carcinogenesis and identify potential therapeutic targets for HPV-related cancers, integrative analyses of m6A regulators in 1,485 head and neck squamous cell carcinoma (HNSC) patients and 507 cervical squamous cell carcinoma (CESC) patients was performed and identified that an m6A regulator, METTL3, was highly expressed in tumors and was related to the poor prognosis in HNSC and CESC. In HPV-positive tumors, METTL3 was positively associated with tumor HPV status, such as HPV integration status, E6 and unspliced-E6 expression, and p16 expression. Further analysis demonstrated that METTL3 high status was negatively correlated with tumor immune cell infiltrations and facilitated the expression of immunosuppressive immune checkpoint molecules (i.e., PD-L1). Cell-derived xenograft models demonstrated that METTL3 inhibitor combined with anti-PD1 therapy promoted immunotherapy of CESC in vivo. Overall, this study identified that METTL3 high status, is associated with poor prognosis and HPV status, and serves as a mediator of the immunosuppressive tumor microenvironment in HPV-associated cancer, which provides a promising therapeutic target for anti-cancer immunotherapy.
Keywords: m6A, HPV, tumor immune microenvironment, HNSC, CESC, METTL3