PMID- 34777365 OWN - NLM STAT- MEDLINE DCOM- 20220225 LR - 20230701 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Slit2-Mediated Metabolic Reprogramming in Bone Marrow-Derived Macrophages Enhances Antitumor Immunity. PG - 753477 LID - 10.3389/fimmu.2021.753477 [doi] LID - 753477 AB - Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response. CI - Copyright (c) 2021 Kaul, Benej, Mishra, Ahirwar, Yadav, Stanford, Jacob, Denko and Ganju. FAU - Kaul, Kirti AU - Kaul K AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Pathology, The Ohio State University, Columbus, OH, United States. FAU - Benej, Martin AU - Benej M AD - Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States. FAU - Mishra, Sanjay AU - Mishra S AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Pathology, The Ohio State University, Columbus, OH, United States. FAU - Ahirwar, Dinesh K AU - Ahirwar DK AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Pathology, The Ohio State University, Columbus, OH, United States. FAU - Yadav, Marshleen AU - Yadav M AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States. FAU - Stanford, Kristin I AU - Stanford KI AD - Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States. FAU - Jacob, Naduparambil K AU - Jacob NK AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States. FAU - Denko, Nicholas C AU - Denko NC AD - Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States. FAU - Ganju, Ramesh K AU - Ganju RK AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. AD - Department of Pathology, The Ohio State University, Columbus, OH, United States. LA - eng GR - R01 CA153490/CA/NCI NIH HHS/United States GR - P30 DK020572/DK/NIDDK NIH HHS/United States GR - R01 CA109527/CA/NCI NIH HHS/United States GR - R01 HL138738/HL/NHLBI NIH HHS/United States GR - R01 CA231857/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20211028 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Polyomavirus Transforming) RN - 0 (CD14 protein, human) RN - 0 (Culture Media, Conditioned) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (Nerve Tissue Proteins) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - R6FXH13RRC (Slit homolog 2 protein) SB - IM MH - Adult MH - Aged MH - Animals MH - Antigens, Polyomavirus Transforming/genetics MH - Culture Media, Conditioned MH - Female MH - Glycolysis/drug effects MH - Humans MH - Intercellular Signaling Peptides and Proteins/genetics/pharmacology/*physiology MH - Lipopolysaccharide Receptors/analysis MH - Macrophage Activation/*drug effects MH - Macrophages/*drug effects/immunology/metabolism MH - Mammary Neoplasms, Experimental/immunology/pathology/*therapy MH - Mammary Tumor Virus, Mouse/genetics MH - Metabolome/*drug effects MH - Mice MH - Mice, Transgenic MH - Middle Aged MH - Monocytes/drug effects/metabolism MH - Nerve Tissue Proteins/genetics/pharmacology/*physiology MH - Radiation Chimera MH - TOR Serine-Threonine Kinases/physiology MH - Triple Negative Breast Neoplasms/blood/chemistry MH - Tumor Burden PMC - PMC8581492 OTO - NOTNLM OT - PyMT OT - Slit2 OT - breast cancer OT - immunometabolism OT - macrophage polarization COIS- NKJ serves as a consultant for Capture Collective Inc. RKG serves as consultant for Guidepoint consultation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/11/16 06:00 MHDA- 2022/02/26 06:00 PMCR- 2021/01/01 CRDT- 2021/11/15 06:58 PHST- 2021/08/04 00:00 [received] PHST- 2021/10/06 00:00 [accepted] PHST- 2021/11/15 06:58 [entrez] PHST- 2021/11/16 06:00 [pubmed] PHST- 2022/02/26 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.753477 [doi] PST - epublish SO - Front Immunol. 2021 Oct 28;12:753477. doi: 10.3389/fimmu.2021.753477. eCollection 2021.