Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects

• Published in: International immunology 2019-03, Vol.31 (4), p.187-198
• Main Authors: Uehara, Takenori, Eikawa, Shingo, Nishida, Mikako, Kunisada, Yuki, Yoshida, Aki, Fujiwara, Tomohiro, Kunisada, Toshiyuki, Ozaki, Toshifumi, Udono, Heiichiro
• Format: Article
• Language: English
• Subjects: Animals; CD11b Antigen - metabolism; Cell Differentiation; Cell Line, Tumor; Cellular Reprogramming; Cytokines - metabolism; Humans; Immunity; Macrophages - immunology; Metformin - metabolism; Mice; Mice, Inbred BALB C; Mice, SCID; Myeloid Cells - immunology; Myeloid-Derived Suppressor Cells - immunology; Original Research; Osteosarcoma - immunology; Oxidative Phosphorylation; Th1 Cells - immunology; Th2 Cells - immunology; Tumor Microenvironment
• ISSN: 1460-2377; 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxy079

Abstract CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors. Metformin reprograms myeloid cell metabolism to enhance anti-tumor immunity