Can we harness the microbiota to enhance the efficacy of cancer immunotherapy?

There is currently much interest in defining how the microbiota shapes immune responses in the context of cancer. Various studies in both mice and humans have associated particular commensal species with better (or worse) outcomes in different cancer types and following treatment with cancer immunotherapies. However, the mechanisms involved remain ill-defined and even controversial. In this Viewpoint, Nature Reviews Immunology has invited six eminent scientists in the field to share their thoughts on the key questions and challenges for the field. In this Viewpoint, six leading experts consider the ways in which the microbiota can influence immune responses to cancer. Immunotherapies have been revolutionary in the treatment of cancer, but will we one day further increase their efficacy with microbiota-derived drugs? B. Brett Finlay is a professor in the Michael Smith Laboratories at the University of British Columbia. His research interests are focused on host–microorganism interactions, at the molecular level, and he has published more than 500 articles. He is a co-author of the books Let Them Eat Dirt and The Whole-Body Microbiome. Romina Goldszmid is an Earl Stadtman Investigator and Head of the Inflammatory Cell Dynamics Section in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, National Institutes of Health (NIH). She received her PhD degree from the University of Buenos Aires, Argentina, and completed her postdoctoral training at the National Institute of Allergy and Infectious Diseases, NIH. She has a long-standing interest in understanding myeloid cell development, differentiation and function in the context of cancer and infections. Current work in her laboratory aims to dissect the myeloid cell repertoire within tumours, determine their contribution to therapy efficacy and unravel the mechanisms by which the microbiota regulates their function. Kenya Honda is a professor at Keio University School of Medicine and a team leader at the RIKEN Center for Integrative Medical Sciences, Japan. His laboratory has been aiming to elucidate and translate the mutualistic relationship between the gut microbiota and the host immune system using gnotobiotic animal models. Giorgio Trinchieri is an NIH Distinguished Investigator and Chief of the Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, NIH. His research has focused for many years on the interplay between inflammation, innate resistance and adaptive immunity and on the role of pro-inflammatory cytokines and interferons in the regulation of haematopoiesis, innate resistance and immunity against infections and tumours. The present focus of his laboratory is on the role of inflammation, innate resistance, immunity and the commensal microbiota in carcinogenesis, cancer progression and prevention of or therapy for cancer. Jennifer Wargo is a professor of surgical oncology and genomic medicine at the University of Texas MD Anderson Cancer Center. She leads the Program for Innovative Microbiome and Translational Research (PRIME-TR) and is internationally recognized for her contributions to cancer research in immunotherapy and the microbiome. Laurence Zitvogel, full professor at Paris-Saclay University, is a research director at INSERM and Scientific Director of the immuno-oncology program at Gustave Roussy, France. She has contributed to the field of cancer immunology and immunotherapy, pioneering the concepts of immunogenic cell death and gut microbiota in cancer.

[1]  N. Socci,et al.  Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  A. Fodor,et al.  VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer , 2013, Scientific Reports.

[3]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[4]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

[5]  W. Garrett,et al.  The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis , 2013, Science.

[6]  Glenn R. Gibson,et al.  The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic , 2014 .

[7]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[8]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[9]  M. Hallek,et al.  Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota , 2016, Oncoimmunology.

[10]  Y. Taur,et al.  Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice , 2016, Science Translational Medicine.

[11]  Noam Shental,et al.  Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine , 2017, Science.

[12]  The New USA NIH Strategic Plan for Complementary and Integrative Health: Interview with Josephine Briggs, MD: Director, National Center for Complementary and Integrative Health (Part 2) , 2017 .

[13]  R. Boidot,et al.  Antibiotic Use Does Not Appear to Influence Response to Nivolumab. , 2017, Anticancer research.

[14]  M. Redinbo,et al.  The role of the microbiome in cancer development and therapy , 2017, CA: a cancer journal for clinicians.

[15]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[16]  A. Schaeffer,et al.  Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy , 2018, Nature Communications.

[17]  Amy Holt,et al.  Host-microbe interactions mediating antitumorigenic effects of MRX0518, a gut microbiota-derived bacterial strain, in breast, renal and lung carcinoma. , 2018 .

[18]  C. Jobin,et al.  Microbiota and cancer immunotherapy: in search of microbial signals , 2018, Gut.

[19]  Weston R. Whitaker,et al.  An exclusive metabolic niche enables strain engraftment in the gut microbiota , 2018, Nature.

[20]  Reducing opioid utilization after urologic oncology surgery. , 2018, Journal of Clinical Oncology.

[21]  J. Wargo,et al.  The gut microbiota influences anticancer immunosurveillance and general health , 2018, Nature Reviews Clinical Oncology.

[22]  L. Zitvogel,et al.  Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  M. Vetizou,et al.  Anti-PD1 in the wonder-gut-land , 2018, Cell Research.

[24]  E. Le Chatelier,et al.  Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients , 2018, Science.

[25]  S. Pushalkar,et al.  The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. , 2018, Cancer discovery.

[26]  C. Pirker,et al.  Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis , 2018, Oncoimmunology.

[27]  B. Helmink,et al.  Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis , 2018, Nature Medicine.

[28]  Rob Knight,et al.  American Gut: an Open Platform for Citizen Science Microbiome Research , 2018, mSystems.

[29]  Jesse H. Arbuckle,et al.  Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair , 2018, Cell.

[30]  Rob Knight,et al.  Regional variation limits applications of healthy gut microbiome reference ranges and disease models , 2018, Nature Medicine.

[31]  D. Jain,et al.  Translocation of a gut pathobiont drives autoimmunity in mice and humans , 2018, Science.

[32]  Itai Sharon,et al.  Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT , 2018, Cell.

[33]  Casey M. Theriot,et al.  Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells , 2018, Science.

[34]  Riyue Bao,et al.  The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients , 2018, Science.

[35]  I. Barshack,et al.  Abstract CT042: Fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402) , 2019, Clinical Trials.

[36]  K. Shannon,et al.  Abstract 2822: Low intestinal microbial diversity is associated with severe immune-related adverse events and lack of response to neoadjuvant combination antiPD1, anti-CTLA4 immunotherapy , 2019, Tumor Biology.

[37]  Abstract CT042: Fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402) , 2019 .

[38]  E. Segal,et al.  The pros, cons, and many unknowns of probiotics , 2019, Nature Medicine.

[39]  A. Bäumler,et al.  Microbiota-Nourishing Immunity: A Guide to Understanding Our Microbial Self. , 2019, Immunity.

[40]  A. Nagrial,et al.  The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies , 2019, Cancer Immunology, Immunotherapy.

[41]  Christine B. Peterson,et al.  Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes , 2019, Cell.

[42]  C. Brock,et al.  Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. , 2019, JAMA oncology.

[43]  Shin-Yeong Kim,et al.  NOD2 Supports Crypt Survival and Epithelial Regeneration after Radiation-Induced Injury , 2019, International journal of molecular sciences.

[44]  N. Waddell,et al.  MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota. , 2019, Immunity.

[45]  D. Plichta,et al.  A defined commensal consortium elicits CD8 T cells and anti-cancer immunity , 2019, Nature.

[46]  L. Zitvogel,et al.  The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  J. McQuade,et al.  Modulating the microbiome to improve therapeutic response in cancer. , 2019, The Lancet. Oncology.

[48]  L. Zitvogel,et al.  The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[49]  B. Helmink,et al.  The microbiome, cancer, and cancer therapy , 2019, Nature Medicine.

[50]  Fecal transplants could help patients on cancer immunotherapy drugs , 2019, Science.

[51]  A. Khoruts,et al.  Durable Long-Term Bacterial Engraftment following Encapsulated Fecal Microbiota Transplantation To Treat Clostridium difficile Infection , 2019, mBio.

[52]  J. McQuade,et al.  Abstract 2838: The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors , 2019, Tumor Biology.

[53]  U. Eriksson,et al.  Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy , 2019, Science.

[54]  P. Gao,et al.  Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients , 2019, Oncoimmunology.

[55]  Richard J. Giannone,et al.  Interspecies Competition Impacts Targeted Manipulation of Human Gut Bacteria by Fiber-Derived Glycans , 2019, Cell.

[56]  T. Powles,et al.  Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials. , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[57]  J. Burton,et al.  P864 Combination of fecal microbiota transplantation from healthy donors with anti-PD1 immunotherapy in treatment-naïve advanced or metastatic melanoma patients , 2020, Journal of Immunotherapy for Cancer.

[58]  Daigo Hashimoto,et al.  Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. , 2020, The New England journal of medicine.