Intra-arterial infusion chemotherapy utilizing cisplatin inhibits bladder cancer by decreasing the fibrocytic myeloid-derived suppressor cells in an m6A-dependent manner

• Published in: Molecular immunology Vol. 137; pp. 28 - 40
• Main Authors: Mu, Xingyu, Wu, Ke, Zhu, Yiwen, Zhu, Youjia, Wang, Yong, Xiao, Liang, Yao, Zhixian, Huang, Wenjie, Sun, Feng, Fan, Jie, Zheng, Zhong, Liu, Zhihong
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.09.2021
• Subjects: Bladder cancer; Cell proliferation; Cisplatin; Immunosuppression; Metastasis; Myeloid-derived suppressor cells; FTO; Cell proliferation; BC; f-MDSC; MDSC; NMIBC; FSP-1; Myeloid-derived suppressor cells; SNE; Metastasis; AP-1; IAIC; Mo-MDSCs; GM-CSF; PMN-MDSC; IDO; FBS; RT-PCR; PD-L1; AKI; TFAP2C; METTL3; 3′-UTR; CFSE; G-CSG; KLF4; TME; EMT; Bladder cancer; Cisplatin; Immunosuppression; SPADE; TIL; Arg; MIBC; m6A; ELISA
• DOI: 10.1016/j.molimm.2021.06.012
• ISSN: 0161-5890

•Intra-arterial infusion chemotherapy (IAIC) utilizing cisplatin could benefit patients with bladder cancer.•Following IAIC, fibrocytic-MDSCs (f-MDSCs) were the immune cell type that were most significantly reduced in number.•The f-MDSCs were found to promote tumor proliferation and metastasis in the BC immune environment.•Cisplatin mediates the immunomodulatory effects of G-CSF by decreasing methylation.•Cisplatin decreased the number of f-MDSCs during IAIC, by blocking G-CSF methylation via targeting METTL3. Intra-arterial infusion chemotherapy (IAIC), using immunomodulatory cisplatin, is a novel treatment for bladder cancer (BC) that allows the delivery of specific drugs to the local malignant lesion. To explore the immunomodulatory effect of cisplatin during IAIC, we detected the proportion of immunosuppressed cells in BC tissue from eight BC patients, with the reduction of myeloid-derived suppressor cells (MDSCs), more specifically fibrocytic-MDSCs (f-MDSCs). Further, we demonstrated that cisplatin inhibits their proliferation and immunosuppressive activity. f-MDSCs promote tumor proliferation and metastasis in the BC immune environment. Then, we analyzed the genetic differences detected in samples before and after chemotherapy and found that granulocyte colony-stimulating factors (G-CSF) decreased after IAIC. Furthermore, G-CSF methylation decreased following treatment with cisplatin. Specifically, treatment with cisplatin decreased the methylase (METTL3) levels in BC cells, which is important for G-CSF production. Collectively, cisplatin decreased the number of f-MDSCs during IAIC, by blocking G-CSF methylation via targeting METTL3.