Advertisement

BioDrugs

pp 1–7 | Cite as

The Impact of the Fecal Microbiome on Cancer Immunotherapy

  • Afaf E. G. Osman
  • Jason J. LukeEmail author
Current Opinion

Abstract

Recent advances in culture-free methods of studying the human microbiome, coupled with strong bioinformatics tools, have provided new insights on the role of the human microbiome in health and disease. The human gut, in particular, houses a vast number and diverse variety of microbes. A plethora of evidence has demonstrated the significant effects of the gut microbiome on local and systemic immunity. Studies in hematopoietic stem cell transplantation recipients provided early evidence of the involvement of the gut microbiome in the development of graft-versus-host disease and its related mortality. Cancer immunotherapy and checkpoint inhibitors, in particular, harness the power of the host’s immune system to fight a range of malignancies. Resistance to immunotherapy and fatal immune-related adverse events both continue to be challenges in the field. The role of the human gut microbiome in affecting the response to immunotherapy was recently uncovered through a series of preclinical and clinical studies. The evidence presented in these studies provides tremendous potential for gut microbes to be used for biomarker development and therapeutic intervention trials.

Notes

Compliance with Ethical Standards

Funding

Jason J. Luke has received the following funding: Department of Defense Career Development Award (W81XWH-17-1-0265), the Arthur J Schreiner Family Melanoma Research Fund, the J. Edward Mahoney Foundation Research Fund, Brush Family Immunotherapy Research Fund, and Buffet Fund for Cancer Immunotherapy.

Conflict of interest

Jason J. Luke declares the following: consultancy—7 Hills, Aduro, Actym, Alphamab Oncology, Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, Compugen, EMD Serono, Gilead, Ideaya, Janssen, Merck, NewLink, Novartis, RefleXion, Spring Bank, Syndax, Tempest, and WntRx; research support (all institutional except as marked)—AbbVie, Array (personal), Boston Biomedical, Bristol-Myers Squibb, Celldex, CheckMate (personal), Corvus, Delcath, Evelo (personal), Five Prime, Genentech, Immunocore, Incyte, MedImmune, Macrogenics, Novartis, Pharmacyclics, Palleon (personal), Merck, Tesaro, and Xencor; travel—Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, EMD Serono, Gilead, Ideaya, Janssen, Merck, NewLink, Novartis, and RefleXion. Patents: Jason J. Luke is a co-inventor on a patent submitted by the University of Chicago covering use of microbiota to improve cancer immunotherapy outcomes. Afaf E.G. Osman declares that she has no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.  https://doi.org/10.1038/nature08821.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369–79.  https://doi.org/10.1056/NEJMra1600266.CrossRefPubMedGoogle Scholar
  3. 3.
    Kim D, Zeng MY, Núñez G. The interplay between host immune cells and gut microbiota in chronic inflammatory diseases. Exp Mol Med. 2017;49(5):e339.  https://doi.org/10.1038/emm.2017.24.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.  https://doi.org/10.1126/science.1240537.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70.  https://doi.org/10.1126/science.1240527.CrossRefPubMedGoogle Scholar
  6. 6.
    Guthrie L, Gupta S, Daily J, Kelly L. Human microbiome signatures of differential colorectal cancer drug metabolism. NPJ Biofilms Microbiomes. 2017;3:27.  https://doi.org/10.1038/s41522-017-0034-1.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974;52(2):401–4.CrossRefGoogle Scholar
  8. 8.
    Jones JM, Wilson R, Bealmear PM. Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras. Radiat Res. 1971;45(3):577–88.CrossRefGoogle Scholar
  9. 9.
    Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, et al. Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol. 2017;35(15):1650–9.  https://doi.org/10.1200/jco.2016.70.3348.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174–82.  https://doi.org/10.1182/blood-2014-02-554725.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, et al. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(8):1373–83.  https://doi.org/10.1016/j.bbmt.2015.04.016.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016.  https://doi.org/10.1126/scitranslmed.aaf2311.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vossen JM, Guiot HF, Lankester AC, Vossen AC, Bredius RG, Wolterbeek R, et al. Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation. PLoS One. 2014;9(9):e105706.  https://doi.org/10.1371/journal.pone.0105706.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Beelen DW, Elmaagacli A, Müller KD, Hirche H, Schaefer UW. Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial. Blood. 1999;93(10):3267–75.PubMedGoogle Scholar
  15. 15.
    Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542–51.  https://doi.org/10.1016/s1470-2045(16)30406-5.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359(6375):582–7.  https://doi.org/10.1126/science.aao4572.CrossRefPubMedGoogle Scholar
  17. 17.
    Chang L, Chang M, Chang HM, Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol. 2018;26(2):e15–21.  https://doi.org/10.1097/pai.0000000000000575.CrossRefPubMedGoogle Scholar
  18. 18.
    Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.  https://doi.org/10.1126/science.aac4255.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.  https://doi.org/10.1126/science.aad1329.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–8.  https://doi.org/10.1126/science.aao3290.CrossRefPubMedGoogle Scholar
  21. 21.
    Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.  https://doi.org/10.1126/science.aan3706.CrossRefPubMedGoogle Scholar
  22. 22.
    Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, 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. Ann Oncol. 2018;29(6):1437–44.  https://doi.org/10.1093/annonc/mdy103.CrossRefPubMedGoogle Scholar
  23. 23.
    Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391.  https://doi.org/10.1038/ncomms10391.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Troy EB, Kasper DL. Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. Front Biosci (Landmark Ed). 2010;15:25–34.CrossRefGoogle Scholar
  25. 25.
    Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368–79.  https://doi.org/10.1093/annonc/mdx108.CrossRefPubMedGoogle Scholar
  26. 26.
    Haro C, Rangel-Zúñiga OA, Alcalá-Díaz JF, Gómez-Delgado F, Pérez-Martínez P, Delgado-Lista J, et al. Intestinal microbiota is influenced by gender and body mass index. PLoS One. 2016;11(5):e0154090.  https://doi.org/10.1371/journal.pone.0154090.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shanahan ER, Shah A, Koloski N, Walker MM, Talley NJ, Morrison M, et al. Influence of cigarette smoking on the human duodenal mucosa-associated microbiota. Microbiome. 2018;6(1):150.  https://doi.org/10.1186/s40168-018-0531-3.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lee AC, Siao-Ping Ong ND. Food-borne bacteremic illnesses in febrile neutropenic children. Hematol Rep. 2011;3(2):e11.  https://doi.org/10.4081/hr.2011.e11.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Thomsen M, Clarke S, Vitetta L. The role of adjuvant probiotics to attenuate intestinal inflammatory responses due to cancer treatments. Benef Microbes. 2018.  https://doi.org/10.3920/bm2017.0172.CrossRefPubMedGoogle Scholar
  30. 30.
    Gonçalves P, Araújo JR, Di Santo JP. A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis. 2018;24(3):558–72.  https://doi.org/10.1093/ibd/izx029.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of MedicineUniversity of ChicagoChicagoUSA

Personalised recommendations