Bachem, Clarke and Kong et al. studied the role of microbiota-derived short chain fatty acids (SCFAs) in an orthotopic melanoma model, revealing a direct link between melanoma control, CD8+ T cell differentiation and SCFA synthetic pathways. Dietary fiber and the SCFA butyrate reduced melanoma progression, increased tumor specific stem-like CD127+CD8+ T cells in the tdLN and induced a FOXO1-driven stemness program. In melanoma patients, metagenomic modeling of fecal samples revealed that increased butyrate flux correlated positively with ICB outcomes, consistent with previously observed correlations with dietary fiber consumption and fecal butyrate levels.
Contributed by Katherine Turner
ABSTRACT: A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8(+) T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127(+)CD8(+) T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127(+)CD8(+) T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8(+) T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8(+) T cells.
Author Info: (1) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. Electronic add
Author Info: (1) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. Electronic address: abachem@unimelb.edu.au. (2) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (3) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Centre for Pathogen Genomics Innovation Hub, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (4) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (5) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (6) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (7) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (8) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, North Rhine-Westphalia 53127, Germany. (9) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (10) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia. (12) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (13) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (14) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (15) Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (16) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (17) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; School of Medicine, University of Western Australia, Crawley, WA 6009, Australia. (18) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (19) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Melbourne Integrative Genomics, School of BioSciences, The University of Melbourne, Melbourne, VIC 3010, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia. (21) Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (22) School of Biomedical Sciences, The University of Western Australia, Perth, WA 6009, Australia; Telethon Kids Institute, The University of Western Australia, Perth, WA 6009, Australia. (23) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Centre for Pathogen Genomics Innovation Hub, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (24) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (25) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (26) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (27) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Institute of Innate Immunity, University of Bonn, Bonn, North Rhine-Westphalia 53127, Germany. Electronic address: sbedoui@unimelb.edu.au.
