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The Microbiome in Immuno-oncology

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Immunotherapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1244))

Abstract

The field of cancer therapy has been revolutionized through the use of immunotherapy, and treatment with these therapies now spans from early to late stage, and even into prevention. However, there are still a significant proportion of patients who do not derive long-term benefit from monotherapy and even combined therapy regimens, and novel approaches are needed to enhance therapeutic responses. Additionally, ideal biomarkers of response to immunotherapy are lacking and are critically needed. An emerging area of interest in immuno-oncology (IO) is the microbiome, which refers to the collection of microbes (and their genomes) that inhabit an individual and live in symbiosis. There is now evidence that these microbes (particularly those within the gut) impact host physiology and can impact responses to immunotherapy. The field of microbiome research in immuno-oncology is quickly emerging, with the potential use of the microbiome (in the gut as well as in the tumor) as a biomarker for response to IO as well as a therapeutic target. Notably, the microbiome may even have a role in toxicity to therapy. The state of the science in microbiome and IO are discussed and caveats and future directions are outlined to provide insights as we move forward as a field.

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References

  1. Turnbaugh PJ, et al. The human microbiome project. Nature. 2007;449(7164):804–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Qin J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. den Besten G, et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54(9):2325–40.

    Article  CAS  Google Scholar 

  4. Morowitz MJ, Carlisle EM, Alverdy JC. Contributions of intestinal bacteria to nutrition and metabolism in the critically ill. Surg Clin North Am. 2011;91(4):771–85.. viii

    Article  PubMed Central  PubMed  Google Scholar 

  5. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Dobell C. The discovery of the intestinal protozoa of man. Proc R Soc Med. 1920;13(Sect Hist Med):1–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Podolsky SH. Metchnikoff and the microbiome. Lancet. 2012;380(9856):1810–1.

    Article  PubMed  Google Scholar 

  8. Kelly CP. Fecal microbiota transplantation--an old therapy comes of age. N Engl J Med. 2013;368(5):474–5.

    Article  CAS  PubMed  Google Scholar 

  9. Fu BC, et al. Characterization of the gut microbiome in epidemiologic studies: the multiethnic cohort experience. Ann Epidemiol. 2016;26(5):373–9.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Zhang J, et al. Evaluation of different 16S rRNA gene V regions for exploring bacterial diversity in a eutrophic freshwater lake. Sci Total Environ. 2018;618:1254–67.

    Article  CAS  PubMed  Google Scholar 

  11. Lee CK, et al. Groundtruthing next-gen sequencing for microbial ecology-biases and errors in community structure estimates from PCR amplicon pyrosequencing. PLoS One. 2012;7(9):e44224.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Caporaso JG, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Segata N, Huttenhower C. Toward an efficient method of identifying core genes for evolutionary and functional microbial phylogenies. PLoS One. 2011;6(9):e24704.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Turnbaugh PJ, Gordon JI. An invitation to the marriage of metagenomics and metabolomics. Cell. 2008;134(5):708–13.

    Article  CAS  PubMed  Google Scholar 

  15. Czesnikiewicz-Guzik M, Muller DN. Scientists on the spot: salt, the microbiome, and cardiovascular diseases. Cardiovasc Res. 2018;114(10):e72–3.

    Article  CAS  PubMed  Google Scholar 

  16. Hansen JJ, Sartor RB. Therapeutic manipulation of the microbiome in IBD: current results and future approaches. Curr Treat Options Gastroenterol. 2015;13(1):105–20.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Jangi S, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Khanna S, et al. Gut microbiome predictors of treatment response and recurrence in primary Clostridium difficile infection. Aliment Pharmacol Ther. 2016;44(7):715–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kim D, Zeng MY, Nunez G. The interplay between host immune cells and gut microbiota in chronic inflammatory diseases. Exp Mol Med. 2017;49(5):e339.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Czerkinsky C, Holmgren J. Enteric vaccines for the developing world: a challenge for mucosal immunology. Mucosal Immunol. 2009;2(4):284–7.

    Article  CAS  PubMed  Google Scholar 

  21. Levine MM. Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol. 2010;8:129.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Prendergast A, Kelly P. Enteropathies in the developing world: neglected effects on global health. Am J Trop Med Hyg. 2012;86(5):756–63.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Verberkmoes NC, et al. Shotgun metaproteomics of the human distal gut microbiota. ISME J. 2009;3(2):179–89.

    Article  CAS  PubMed  Google Scholar 

  24. Ma C, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391)

    Google Scholar 

  25. Yoshimoto S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101.

    Article  CAS  PubMed  Google Scholar 

  26. Kwa M, et al. The intestinal microbiome and estrogen receptor-positive female breast cancer. J Natl Cancer Inst, 2016. 108(8).

    Google Scholar 

  27. Kim OY, et al. Bacterial outer membrane vesicles suppress tumor by interferon-gamma-mediated antitumor response. Nat Commun. 2017;8(1):626.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Zheng JH, et al. Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Sci Transl Med. 2017;9(376)

    Google Scholar 

  29. Boursi B, et al. Recurrent antibiotic exposure may promote cancer formation – another step in understanding the role of the human microbiota? Eur J Cancer. 2015;51(17):2655–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Wang F, et al. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014;345(2):196–202.

    Article  CAS  PubMed  Google Scholar 

  31. Di Domenico EG, et al. Biofilm producing salmonella typhi: chronic colonization and development of gallbladder cancer. Int J Mol Sci. 2017;18(9)

    Google Scholar 

  32. He Z, et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. 2018.

    Google Scholar 

  33. Arthur JC, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Dalmasso G, et al. The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment. Gut Microbes. 2014;5(5):675–80.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Tomkovich S, et al. Locoregional effects of microbiota in a preclinical model of colon carcinogenesis. Cancer Res. 2017;77(10):2620–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Fukugaiti MH, et al. High occurrence of fusobacterium nucleatum and Clostridium difficile in the intestinal microbiota of colorectal carcinoma patients. Braz J Microbiol. 2015;46(4):1135–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Rubinstein MR, et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14(2):195–206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Banerjee S, et al. The ovarian cancer oncobiome. Oncotarget. 2017;8(22):36225–45.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Ferreira RM, et al. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut. 2018;67(2):226–36.

    Article  CAS  PubMed  Google Scholar 

  40. Mao Q, et al. Interplay between the lung microbiome and lung cancer. Cancer Lett. 2018;415:40–8.

    Article  CAS  PubMed  Google Scholar 

  41. Pushalkar S, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8(4):403–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Sfanos KS, et al. A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms. Prostate. 2008;68(3):306–20.

    Article  CAS  PubMed  Google Scholar 

  43. Urbaniak C, et al. The microbiota of breast tissue and its association with breast cancer. Appl Environ Microbiol. 2016;82(16):5039–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ishaq S, Nunn L. Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench. 2015;8(Suppl 1):S6–S14.

    PubMed Central  PubMed  Google Scholar 

  45. Cronin M, et al. Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors. Mol Ther. 2010;18(7):1397–407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Chung L, et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe. 2018;23(2):203–14.. e5

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.

    Article  CAS  PubMed  Google Scholar 

  48. Matson V, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.

    Article  CAS  PubMed  Google Scholar 

  50. Brand A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657–71.

    Article  CAS  PubMed  Google Scholar 

  51. Thiele Orberg E, et al. The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis. Mucosal Immunol. 2017;10(2):421–33.

    Article  CAS  PubMed  Google Scholar 

  52. Geller LT, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Yu G, et al. Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features. Genome Biol. 2016;17(1):163.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Panda A, et al. Immune activation and benefit from avelumab in EBV-positive gastric cancer. J Natl Cancer Inst. 2018;110(3):316–20.

    Article  CAS  PubMed  Google Scholar 

  55. Riquelme E, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178(4):795–806 e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Belkaid Y, Naik S. Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol. 2013;14(7):646–53.

    Article  CAS  PubMed  Google Scholar 

  57. Gorjifard S, Goldszmid RS. Microbiota-myeloid cell crosstalk beyond the gut. J Leukoc Biol. 2016;100(5):865–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Francino MP. Early development of the gut microbiota and immune health. Pathogens. 2014;3(3):769–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Shanahan F. Physiological basis for novel drug therapies used to treat the inflammatory bowel diseases I. Pathophysiological basis and prospects for probiotic therapy in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2005;288(3):G417–21.

    Article  CAS  PubMed  Google Scholar 

  60. Thomas CM, Versalovic J. Probiotics-host communication: modulation of signaling pathways in the intestine. Gut Microbes. 2010;1(3):148–63.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12(12):821–32.

    Article  CAS  PubMed  Google Scholar 

  62. Levy M, et al. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219–32.

    Article  CAS  PubMed  Google Scholar 

  63. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010;107(27):12204–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Sivan A, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Vetizou M, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Chaput N, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368–79.

    Article  CAS  PubMed  Google Scholar 

  67. Frankel AE, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017;19(10):848–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Routy B, et al. The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation. Oncoimmunology. 2017;6(1):e1258506.

    Article  CAS  PubMed  Google Scholar 

  69. Gharaibeh RZ, Jobin C. Microbiota and cancer immunotherapy: in search of microbial signals. Gut. 2018.

    Google Scholar 

  70. Dubin K, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 2016;7:10391.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Golob JL, et al. Stool microbiota at neutrophil recovery is predictive for severe acute graft vs host disease after hematopoietic cell transplantation. Clin Infect Dis. 2017;65(12):1984–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Jenq RR, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012;209(5):903–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Liu C, et al. Associations between acute gastrointestinal GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell transplant recipients and donors. Bone Marrow Transplant. 2017;52(12):1643–50.

    Article  CAS  PubMed  Google Scholar 

  74. Weber D, et al. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood. 2015;126(14):1723–8.

    Article  CAS  PubMed  Google Scholar 

  75. Abedon ST, et al. Editorial: phage therapy: past, present and future. Front Microbiol. 2017;8:981.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Budynek P, et al. Bacteriophages and cancer. Arch Microbiol. 2010;192(5):315–20.

    Article  CAS  PubMed  Google Scholar 

  77. Hibberd AA, et al. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 2017;4(1):e000145.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Pranjol MZ, Hajitou A. Bacteriophage-derived vectors for targeted cancer gene therapy. Viruses. 2015;7(1):268–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Ramirez-Farias C, et al. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br J Nutr. 2009;101(4):541–50.

    Article  CAS  PubMed  Google Scholar 

  80. Wong WF, Santiago M. Microbial approaches for targeting antibiotic-resistant bacteria. Microb Biotechnol. 2017;10(5):1047–53.

    Article  PubMed Central  PubMed  Google Scholar 

  81. Baruch EN, 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). AACR; Cancer Res, 2019. 79((13 Suppl)).

    Google Scholar 

  82. McQuade JL, et al. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 2019;20(2):e77–91.

    Article  PubMed  Google Scholar 

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Acknowledgments

J.A.W. is supported by the NIH (1 R01 CA219896-01A1), U.S Israel Binational Science Foundation (201332), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17), Department of Defense (W81XWH-16-1-0121), MD Anderson Cancer Center Multidisciplinary Research Program Grant, Andrew Sabin Family Fellows Program, and MD Anderson Cancer Center’s Melanoma Moon Shots Program. J.A.W. is a member of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center. Figures were prepared using Biorender.com.

Conflict of Interest

J. Wargo is an inventor on a US patent application (PCT/US17/53.717) submitted by the University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. He reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, and Bristol-Myers Squibb. He serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, and Microbiome DX. J. Wargo also receives research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis.

The other authors declared no conflict of interest.

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Author notes

  1. Joseph Toker and Reetakshi Arora contributed equally with all other contributors.

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Joseph Toker, Reetakshi Arora & Jennifer A. Wargo

  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jennifer A. Wargo

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  1. Joseph Toker
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  2. Reetakshi Arora
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  3. Jennifer A. Wargo
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Correspondence to Jennifer A. Wargo .

Editor information

Editors and Affiliations

  1. MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    Aung Naing

  2. Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Joud Hajjar

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Toker, J., Arora, R., Wargo, J.A. (2020). The Microbiome in Immuno-oncology. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 1244. Springer, Cham. https://doi.org/10.1007/978-3-030-41008-7_19

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