Myeloid-derived suppressor cells are essential partners for immune checkpoint inhibitors in the treatment of cisplatin-resistant bladder cancer. (1st June 2020)

• Record Type: Journal Article
• Authors: Takeyama, Yuji; Kato, Minoru; Tamada, Satoshi; Azuma, Yukari; Shimizu, Yasuomi; Iguchi, Taro; Yamasaki, Takeshi; Gi, Min; Wanibuchi, Hideki; Nakatani, Tatsuya
• Is Part Of: Cancer letters. Volume 479(2020)
• Page Start: 89
• Page End: 99
• Publication Date: 2020-06-01
• Subjects: Combination immunotherapy -- Cisplatin resistance -- MDSCs -- PD-L1 -- Chemokine; Arg-1 arginase 1 -- BCG Bacillius Calmette-Guerin -- CAF cancer associated fibroblasts -- CTLA-4 cytotoxic T-lymphocyte-associated protein 4 -- ICI immune checkpoint inhibitors -- i.p. intra-peritoneally -- MDSCs myeloid-derived suppressor cells -- Mo-MDSCs monocytic MDSCs -- MRCs myeloid regulatory cells -- iNOS nitric oxide synthase 2 -- PMN-MDSCs polymorphonuclear MDSCs -- ROS reactive oxygen species -- TAMs tumor-associated macrophages; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.03.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers. Highlights: Chemokines inducing MDSCs were highly secreted by cisplatin-resistant bladder cancer cells. MDSCs have strong immunosuppressive function in the tumor microenvironment. Treatments targeting MDSCs enhance the effect of immune checkpoint inhibitors.