Metabolomic profiling of tumor-infiltrating macrophages during tumor growth
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ORIGINAL ARTICLE
Metabolomic profiling of tumor‑infiltrating macrophages during tumor growth Naoki Umemura1 · Masahiro Sugimoto2,3 · Yusuke Kitoh4 · Masanao Saio5 · Hiroshi Sakagami6 Received: 28 August 2019 / Accepted: 22 May 2020 © The Author(s) 2020
Abstract Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSClike cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity. Keywords Myeloid derived suppressor cells · Tumor infiltrating macrophages · Metabolomics · Tumor necrosis factoralpha
Introduction * Naoki Umemura [email protected]‑u.ac.jp 1
Department of Oral Biochemistry, Asahi University School of Dentistry, Gifu 501‑0296, Japan
2
Health Promotion and Preemptive Medicine, Research and Development Center for Minimally Invasive Therapies, Institute of Medical Sciences, Tokyo Medical University, Tokyo, Japan
3
Institute for Advanced Biosciences, Keio University, Yamagata, Japan
4
Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan
5
Graduate School of Health Sciences, Gunma University, Maebashi, Gunma, Japan
6
Meikai University Research Institute of Odontology (M-RIO), Saitama, Japan
Previous studies have shown that host immune mechanisms are not entirely effective against tumors, probably due to the acquisition of immune escape mechanisms by tumor cells or T cell intolerance in tumor tissue
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