YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer
Hao Jin,
Yue Chen,
Dongbo Zhang,
Junfan Lin,
Songyin Huang,
Xiaohua Wu,
Wen Deng,
Jiandong Huang,
Yandan Yao
Affiliations
Hao Jin
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Yue Chen
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Dongbo Zhang
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Junfan Lin
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Songyin Huang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Xiaohua Wu
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Wen Deng
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
Jiandong Huang
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province 518055, China; Clinical Oncology Center, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China; Corresponding author
Yandan Yao
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China; Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong Province 516621, China; Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong Province 516621, China; Corresponding author
Summary: Patients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.
