Skip to main content

Advertisement

SpringerLink
Log in

Association of the gut microbiome with cancer immunotherapy

  • Invited Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Immune checkpoint inhibitors, programmed cell death-1- and cytotoxic T-lymphocyte-associated protein 4-based immunotherapy have remarkably improved survival with durable response for patients with multiple cancer type. The accurate predictors of response and toxicity to immunotherapy are still unclear and have been focused on the gut microbiome. The gut microbiome, which refers to the microorganisms and their genes, affects the host immunity both locally and systemically. Modulation of the gut microbiota alters the immune systems and affects the efficacy of immune checkpoint inhibitor. In this review, we investigate the evidence on the role of the microbiome in cancer patients and discuss the impact of microbiome on the efficacy of immune checkpoint inhibitors in cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384

    Article  CAS  PubMed  Google Scholar 

  3. Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330

    Article  CAS  PubMed  Google Scholar 

  4. O’Donnell JS, Long GV, Scolyer RA et al (2017) Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev 52:71–81

    Article  CAS  PubMed  Google Scholar 

  5. Frankel AE, Coughlin LA, Kim J et al (2017) Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 19:848–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chaput N, Lepage P, Coutzac C et al (2017) Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 28:1368–1379

    Article  CAS  PubMed  Google Scholar 

  7. Routy B, Le Chatelier E, Derosa L et al (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91–97

    Article  CAS  PubMed  Google Scholar 

  8. Gopalakrishnan V, Spencer CN, Nezi L et al (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:97–103

    Article  CAS  PubMed  Google Scholar 

  9. Matson V, Fessler J, Bao R et al (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:104–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541:321–330

    Article  CAS  PubMed  Google Scholar 

  11. Guarner F, Malagelada JR (2003) Gut flora in health and disease. Lancet 361:512–519

    Article  PubMed  Google Scholar 

  12. Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–848

    Article  CAS  PubMed  Google Scholar 

  13. Tremaroli V, Bäckhed F (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489:242–249

    Article  CAS  PubMed  Google Scholar 

  14. Imhann F, Bonder MJ, Vila AV et al (2016) Proton pump inhibitors affect the gut microbiome. Gut 65:740–748

    Article  CAS  PubMed  Google Scholar 

  15. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13:800–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kostic AD, Chun E, Robertson L et al (2013) Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14:207–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533

    Article  PubMed  PubMed Central  Google Scholar 

  18. Honda K, Littman DR (2016) The microbiota in adaptive immune homeostasis and disease. Nature 535:75–84

    Article  CAS  PubMed  Google Scholar 

  19. Janeway CA Jr (2013) Pillars article: approaching the asymptote? Evolution and revolution in immunology. Cold spring harb symp quant biol. 1989. 54: 1–13. J Immunol 191:4475–4487

    CAS  PubMed  Google Scholar 

  20. Lathrop SK, Bloom SM, Rao SM et al (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stary G, Olive A, Radovic-Moreno AF et al (2015) VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fagarasan S, Muramatsu M, Suzuki K et al (2002) Critical roles of activation-induced cytidine deaminase in the homeostasis of gut fora. Science 298:1424–1427

    Article  CAS  PubMed  Google Scholar 

  23. Wei B, Su TT, Dalwadi H et al (2008) Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells. Eur J Immunol 38:3411–3425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mantis NJ, Rol N, Corthésy B (2001) Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol 4:603–611

    Article  Google Scholar 

  25. Mathias A, Pais B, Favre L et al (2014) Role of secretory IgA in the mucosal sensing of commensal bacteria. Gut Microbes 5:688–695

    Article  PubMed  PubMed Central  Google Scholar 

  26. Frosali S, Pagliari D, Gambassi G et al (2015) How the intricate interaction among toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res 2015:489821

    Article  PubMed  PubMed Central  Google Scholar 

  27. Coley WB (1910) The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigious). Proc R Soc Med 3:1–48

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ranf S (2016) Immune sensing of lipopolysaccharide in plants and animals: same but different. PLoS Pathog 12:e1005596

    Article  PubMed  PubMed Central  Google Scholar 

  30. Morrissey D, O’Sullivan GC, Tangney M (2010) Tumour targeting with systemically administered bacteria. Curr Gene Ther 10:3–14

    Article  CAS  PubMed  Google Scholar 

  31. Roberts NJ, Zhang L, Janku F et al (2014) Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 6:249ra111

    Article  PubMed  PubMed Central  Google Scholar 

  32. Stern C, Kasnitz N, Kocijancic D et al (2015) Induction of CD4(+) and CD8(+) anti-tumor effector T cell responses by bacteria mediated tumor therapy. Int J Cancer 137:2019–2028

    Article  CAS  PubMed  Google Scholar 

  33. Akrami M, Menzies R, Chamoto K et al (2020) Circulation of Gut-preactivated naïve CD8+ T cells enhances antitumor immunity in B cell-defective mice. Proc Natl Acad Sci USA 117:23674–23683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sivan A, Corrales L, Hubert N et al (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vetizou M, Pitt JM, Daillere R et al (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079–1084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Viaud S, Saccheri F, Mignot G et al (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Uribe-Herranz M, Bittinger K, Rafail S et al (2018) Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12. JCI Insight 3:94952

    Article  PubMed  Google Scholar 

  38. Colbert LE, Previs R, Medrano AYD et al (2017) Rectal microbiome diversity predicts disease response at completion of radiation therapy for squamous cell carcinoma of the cervix. Int J Radiat Oncol Biol Phys 99:S51

    Article  Google Scholar 

  39. Lange K, Buerger M, Stallmach A et al (2016) Effects of antibiotics on gut microbiota. Dig Dis 34:260–268

    Article  PubMed  Google Scholar 

  40. Dethlefsen L, Relman DA (2011) Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA 108:4554–4561

    Article  CAS  PubMed  Google Scholar 

  41. Dethlefsen L, Huse S, Sogin ML et al (2008) The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6:e280

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jernberg C, Lofmark S, Edlund C et al (2007) Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 1:56–66

    Article  CAS  PubMed  Google Scholar 

  43. Heinsen F-A, Knecht H, Neulinger SC et al (2015) Dynamic changes of the luminal and mucosa-associated gut microbiota during and after antibiotic therapy with paromomycin. Gut Microbes 6:243–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Looft T, Johnson TA, Allen HK et al (2012) In-feed antibiotic effects on the swine intestinal microbiome. Proc Natl Acad Sci USA 109:1691–1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Derosa L, Hellmann MD, Spaziano M et al (2018) 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 29:1437–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hakozaki T, Okuma Y, Omori M et al (2019) Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett 17:2946–2952

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kaderbhai C, Richard C, Fumet JD et al (2017) Antibiotic use does not appear to influence response to nivolumab. Anticancer Res 37:3195–3200

    CAS  PubMed  Google Scholar 

  48. Falony G, Joossens M, Vieira-Silva S et al (2016) Population-level analysis of gut microbiome variation. Science 352:560–564

    Article  CAS  PubMed  Google Scholar 

  49. Jackson MA, Goodrich JK, Maxan M-E et al (2016) Proton pump inhibitors alter the composition of the gut microbiota. Gut 65:749–756

    Article  PubMed  Google Scholar 

  50. Forslund K, Hildebrand F, Nielsen T et al (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. van Nood E, Dijkgraaf MG, Keller JJ (2013) Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med 368:2145

    PubMed  Google Scholar 

  52. Paramsothy S, Kamm MA, Kaakoush NO et al (2017) Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389:1218–1228

    Article  PubMed  Google Scholar 

  53. Vrieze A, Van Nood E, Holleman F et al (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143:913-916.e7

    Article  CAS  PubMed  Google Scholar 

  54. Baruch EN, Youngster I, Ben-Betzalel G et al (2021) Fecal microbiota transplant promotes response in immuno-therapy-refractory melanoma patients. Science 371:602–609

    Article  CAS  PubMed  Google Scholar 

  55. Davar D, Dzutsev AK, McCulloch JA et al (2021) Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 371:595–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tomita Y, Ikeda T, Sakata S et al (2020) Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol Res 8:1236–1242

    Article  CAS  PubMed  Google Scholar 

  57. Takada K, Shimokawa M, Takamori S et al (2021) Clinical impact of probiotics on the efficacy of anti-PD-1 monotherapy in patients with nonsmall cell lung cancer: a multicenter retrospective survival analysis study with inverse probability of treatment weighting. Int J Cancer 149:473–482

    Article  CAS  PubMed  Google Scholar 

  58. Bäckhed F, Ley RE, Sonnenburg JL et al (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920

    Article  PubMed  Google Scholar 

  59. Ma N, Guo P, Zhang J et al (2018) Nutrients mediate intestinal bacteria-mucosal immune crosstalk. Front Immunol 9:5

    Article  PubMed  PubMed Central  Google Scholar 

  60. Shortt C, Hasselwander O, Meynier A et al (2018) Systematic review ofthe efects of the intestinal microbiota on selected nutrients and non-nutrients. Eur J Nutr 57:25–49

    Article  CAS  PubMed  Google Scholar 

  61. Nomura M, Nagatomo R, Doi K et al (2020) Association of short-chain fatty acids in the Gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw Open 3:e202895

    Article  PubMed  PubMed Central  Google Scholar 

  62. Coutzac C, Jouniaux JM, Paci A et al (2020) Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun 11:2168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Smith PM, Howitt MR, Panikov N et al (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573

    Article  CAS  PubMed  Google Scholar 

  64. Furusawa Y, Obata Y, Fukuda S et al (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450

    Article  CAS  PubMed  Google Scholar 

  65. Arpaia N, Campbell C, Fan X et al (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moriyama M, Ichinohe T (2019) High ambient temperature dampens adaptive immune responses to influenza A virus infection. Proc Natl Acad Sci USA 116:3118–3125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fellows R, Denizot J, Stellato C et al (2018) Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9:105

    Article  PubMed  PubMed Central  Google Scholar 

  68. Yuille S, Reichardt N, Panda S et al (2018) Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid. PLoS One 13:e0201073

    Article  PubMed  PubMed Central  Google Scholar 

  69. Woods DM, Sodré AL, Villagra A et al (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3:1375–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rinninella E, Cintoni M, Raoul P et al (2019) Food components and dietary habits: keys for a healthy gut microbiota composition. Nutrients 11:2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. O’Keefe SJ, Li JV, Lahti L et al (2015) Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun 6:6342

    Article  CAS  PubMed  Google Scholar 

  72. Wu GD, Chen J, Hoffmann C et al (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. De Filippo C, Cavalieri D, Di Paola M et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 107:14691–14696

    Article  PubMed  PubMed Central  Google Scholar 

  74. Baxter NT, Schmidt AW, Venkataraman A et al (2019) Dynamics of human gut microbiota and short-chain fatty acids in response to dietary interventions with three fermentable fibers. MBio 10:e02566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Spencer CN, McQuade JL, Gopalakrishnan V et al (2021) Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 374:1632–1640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

None declared.

Author information

Authors and Affiliations

  1. Department of Clinical Oncology, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Motoo Nomura

Authors
  1. Motoo Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Motoo Nomura.

Ethics declarations

Conflict of interest

Motoo Nomura declares no potential conflicts of interest and has no financial disclosures.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nomura, M. Association of the gut microbiome with cancer immunotherapy. Int J Clin Oncol 28, 347–353 (2023). https://doi.org/10.1007/s10147-022-02180-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-022-02180-2

Keywords

Search

Navigation