Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response
Christine N Spencer, Jennifer L McQuade, Vancheswaran Gopalakrishnan, John A McCulloch, Marie Vetizou, Alexandria P Cogdill, Md A Wadud Khan, Xiaotao Zhang, Michael G White, Christine B Peterson, Matthew C Wong, Golnaz Morad, Theresa Rodgers, Jonathan H Badger, Beth A Helmink, Miles C Andrews, Richard R Rodrigues, Andrey Morgun, Young S Kim, Jason Roszik, Kristi L Hoffman, Jiali Zheng, Yifan Zhou, Yusra B Medik, Laura M Kahn, Sarah Johnson, Courtney W Hudgens, Khalida Wani, Pierre-Olivier Gaudreau, Angela L Harris, Mohamed A Jamal, Erez N Baruch, Eva Perez-Guijarro, Chi-Ping Day, Glenn Merlino, Barbara Pazdrak, Brooke S Lochmann, Robert A Szczepaniak-Sloane, Reetakshi Arora, Jaime Anderson, Chrystia M Zobniw, Eliza Posada, Elizabeth Sirmans, Julie Simon, Lauren E Haydu, Elizabeth M Burton, Linghua Wang, Minghao Dang, Karen Clise-Dwyer, Sarah Schneider, Thomas Chapman, Nana-Ama A S Anang, Sheila Duncan, Joseph Toker, Jared C Malke, Isabella C Glitza, Rodabe N Amaria, Hussein A Tawbi, Adi Diab, Michael K Wong, Sapna P Patel, Scott E Woodman, Michael A Davies, Merrick I Ross, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Vanessa Jensen, Yardena Samuels, Ravid Straussman, Nadim J Ajami, Kelly C Nelson, Luigi Nezi, Joseph F Petrosino, P Andrew Futreal, Alexander J Lazar, Jianhua Hu, Robert R Jenq, Michael T Tetzlaff, Yan Yan, Wendy S Garrett, Curtis Huttenhower, Padmanee Sharma, Stephanie S Watowich, James P Allison, Lorenzo Cohen, Giorgio Trinchieri, Carrie R Daniel, Jennifer A Wargo, Christine N Spencer, Jennifer L McQuade, Vancheswaran Gopalakrishnan, John A McCulloch, Marie Vetizou, Alexandria P Cogdill, Md A Wadud Khan, Xiaotao Zhang, Michael G White, Christine B Peterson, Matthew C Wong, Golnaz Morad, Theresa Rodgers, Jonathan H Badger, Beth A Helmink, Miles C Andrews, Richard R Rodrigues, Andrey Morgun, Young S Kim, Jason Roszik, Kristi L Hoffman, Jiali Zheng, Yifan Zhou, Yusra B Medik, Laura M Kahn, Sarah Johnson, Courtney W Hudgens, Khalida Wani, Pierre-Olivier Gaudreau, Angela L Harris, Mohamed A Jamal, Erez N Baruch, Eva Perez-Guijarro, Chi-Ping Day, Glenn Merlino, Barbara Pazdrak, Brooke S Lochmann, Robert A Szczepaniak-Sloane, Reetakshi Arora, Jaime Anderson, Chrystia M Zobniw, Eliza Posada, Elizabeth Sirmans, Julie Simon, Lauren E Haydu, Elizabeth M Burton, Linghua Wang, Minghao Dang, Karen Clise-Dwyer, Sarah Schneider, Thomas Chapman, Nana-Ama A S Anang, Sheila Duncan, Joseph Toker, Jared C Malke, Isabella C Glitza, Rodabe N Amaria, Hussein A Tawbi, Adi Diab, Michael K Wong, Sapna P Patel, Scott E Woodman, Michael A Davies, Merrick I Ross, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Vanessa Jensen, Yardena Samuels, Ravid Straussman, Nadim J Ajami, Kelly C Nelson, Luigi Nezi, Joseph F Petrosino, P Andrew Futreal, Alexander J Lazar, Jianhua Hu, Robert R Jenq, Michael T Tetzlaff, Yan Yan, Wendy S Garrett, Curtis Huttenhower, Padmanee Sharma, Stephanie S Watowich, James P Allison, Lorenzo Cohen, Giorgio Trinchieri, Carrie R Daniel, Jennifer A Wargo
Abstract
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
Conflict of interest statement
Competing interests: J.A.W., V.G., and M.C.A. are inventors on patent WO2020106983A1 submitted by the Board of Regents, The University of Texas System, and Institut Gustav Roussy that covers methods and compositions for treating cancer and for predicting a subject’s response to combination checkpoint inhibitor therapy. J.A.W. and V.G. are inventors and C.N.S. is a collaborator on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance ICB responses by modulating the microbiome. J.A.W. and R.R.J. are inventors on patent WO2020150429A1 submitted by the Board of Regents, The University of Texas System, that covers methods and compositions for treating immune checkpoint inhibitor (ICI)–associated colitis in a subject through the administration of fecal matter from a healthy donor to the subject. R.R.J. is an inventor on patent WO2016086161A1 submitted by the Memorial Sloan Kettering Cancer Center that covers compositions and methods for increasing the abundance of commensal bacteria belonging to the order Clostridiales that are associated with reduced lethal graft-versus-host disease and improved overall survival after bone marrow or hematopoietic stem cell transplant. R.R.J. is an inventor on patent WO2017041039A1 submitted by Memorial Sloan Kettering Cancer Center that covers methods and compositions for reducing the risk of cancer relapse in a subject who has received cancer treatment. J.A.W. reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, Med Immune, and Bristol-Myers Squibb and serves as a consultant and/or advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, Microbiome DX, and Micronoma. J.A.W. also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis. V.G. reports honoraria from Expert Connect and Kansas Society of Clinical Oncology. J.L.M. reports advisory board participation and honoraria from Bristol-Myers Squibb, Merck, and Roche/Genentech. M.C.A. reports advisory board participation, honoraria, and research funding to their institution from MSD Australia, outside the submitted work, and contract research for BMS Australia, outside the current work. A.P.C. is an employee and equity holder at Immunai. A.P.C. serves as an advisory member and holds equity in Vastbiome. G.Mo. is a coinventor on US patents (PCT/US2019/022194, PCT/US2020/029556, and PCT/US2020/046050) not related to the content of this paper. M.I.R. reports paid consultant position for AMGEN and paid consultant and advisory board membership for MERCK. I.C.G. reports research support from Bristol-Myers Squibb and Merck. I.C.G. serves as a consultant for Bristol-Myers Squibb, Array, and Novartis. R.N.A. receives research funding from Merck, Bristol-Myers Squibb, Genentech, Novartis, and Iovance. J.E.G. is a consultant and/or is on the advisory board for Merck, Regeneron, Syndex, Novartis, and Bristol-Myers Squibb, unrelated to the content of this work. R.R.J. is an advisor and holds equity in Seres Therapeutics and Kaleido Biosciences; serves on the advisory board of MaaT Pharma, LISCure Biosciences, and Prolacta Biosciences; and consults for Davolterra, Merck, Microbiome DX, and Karius. C.H. is on the scientific advisory board for Seres Therapeutics and Empress Therapeutics. M.K.W. is on the advisory boards of Merck, Pfizer, Bristol Myers Squibb, Regeneron, EMD-Serono, ExiCure, Castle Biosciences, and Adagene. H.A.T. is a consultant for BMS, Merck, Novartis, Genentech, Eisai, Iovance, Karyopharm, and Pfizer and reports research funding to institution from BMS, Merck, Novartis, Genentech, GSK, and Dragonfly. A.D. serves as a consultant for Nektar, MultiVir, Idera, Array, and Bristol-Myers Squibb. P.S. reports consulting or stock ownership or advisory board for Achelois, Adaptive Biotechnologies, Affini-T, Apricity, BioAtla, BioNTech, Candel Therapeutics, Catalio, Codiak, Constellation, Dragonfly, Earli, Enable Medicine, Glympse, Hummingbird, ImaginAb, Infinity Pharma, Jounce, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic AI, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. J.P.A. reports consulting, stock ownership, or advisory board membership for Achelois, Adaptive Biotechnologies, Apricity, BioAtla, BioNTech, Candel Therapeutics, Codiak, Dragonfly, Earli, Enable Medicine, Hummingbird, ImaginAb, Jounce, Lava Therapeutics, Lytix, Marker, PBM Capital, Phenomic AI, Polaris Pharma, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, and ABM Therapeutics, and he has been the principal investigator of research grants to MD Anderson from Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. P.H. is on the scientific advisory board for Dragonfly and Immatics. M.I.R. is on the melanoma advisory board for Merck and is a paid consultant for AMGEN and Merck. S.P.P. reports institutional clinical trial support from NCI, Merck, and Bristol Myers Squibb during the conduct of the study; institutional clinical trial support from Reata Pharmaceuticals, Novartis, Deciphera, Provectus Biopharmaceuticals, Foghorn Therapeutics, TriSalus Life Sciences, and Seattle Genetics; advisory board honoraria from Castle Biosciences and TriSalus Life Sciences; honoraria as Peer Discussion Group Leader for Merck; and honoraria for service as Chair of International Data Monitoring Committee for Immunocore, outside the submitted work.
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Source: PubMed