Ding and Shrestha et al. used whole beta-glucan particles (WGP) to induce trained immunity against tumor cells in myeloid cells, a pro-tumor cell type known to be enhanced in pre-metastatic niches. One i.p. dose of WGP increased bone marrow (BM) myelopoiesis and trained lung interstitial macrophages via sphingosine-mitochondrial fission, enhancing their phagocytic and cytotoxic capacity and control of tumor metastasis in various mouse models, independent of neutrophils and T and B cells. Adoptive transfer of central trained BM-derived macrophages also reduced tumor metastasis. Human monocytes trained with WGP reduced tumor burden in NSG mice.
Contributed by Ute Burkhardt
ABSTRACT: Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.
Author Info: (1) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisvil
Author Info: (1) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (2) Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. (3) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (4) Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. (5) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (6) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. (7) Department of Chemistry, Indiana University, Bloomington, IN, USA. (8) Department of Chemistry, Lehigh University, Bethlehem, PA, USA. (9) Department of Chemistry, University of Louisville, Louisville, KY, USA. (10) Department of Chemistry, University of Louisville, Louisville, KY, USA. (11) Department of Neuroscience, KBRIN Bioinformatics Core, University of Louisville, Louisville, KY, USA. (12) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (13) Functional Immunomics Core, Brown Cancer Center, University of Louisville, Louisville, KY, USA. (14) Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA. (15) Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. (16) Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA. Department of Computer Science and Engineering, University of Louisville, Louisville, KY, USA. (17) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (18) Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA. (19) Department of Chemistry, University of Louisville, Louisville, KY, USA. (20) Department of Chemistry, Lehigh University, Bethlehem, PA, USA. (21) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. (22) Department of Chemistry, Indiana University, Bloomington, IN, USA. (23) Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. jun.yan@louisville.edu. Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. jun.yan@louisville.edu.
