DOI QR코드

DOI QR Code

Commensal Microbiota and Cancer Immunotherapy: Harnessing Commensal Bacteria for Cancer Therapy

  • Jihong Bae (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Kwangcheon Park (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • You-Me Kim (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST))
  • 투고 : 2022.01.23
  • 심사 : 2022.02.07
  • 발행 : 2022.02.28

초록

Cancer is one of the leading causes of death worldwide and the number of cancer patients is expected to continuously increase in the future. Traditional cancer therapies focus on inhibiting cancer growth while largely ignoring the contribution of the immune system in eliminating cancer cells. Recently, better understanding of immunological mechanisms pertaining to cancer progress has led to development of several immunotherapies, which revolutionized cancer treatment. Nonetheless, only a small proportion of cancer patients respond to immunotherapy and maintain a durable response. Among multiple factors contributing to the variability of immunotherapy response rates, commensal microbiota inhabiting patients have been identified as one of the most critical factors determining the success of immunotherapy. The functional diversity of microbiota differentially affects the host immune system and controls the efficacy of immunotherapy in individual cancer patients. Moreover, clinical studies have demonstrated that changing the gut microbiota composition by fecal microbiota transplantation in patients who failed a previous immunotherapy converts them to responders of the same therapy. Consequently, both academic and industrial researchers are putting extensive efforts to identify and develop specific bacteria or bacteria mixtures for cancer immunotherapy. In this review, we will summarize the immunological roles of commensal microbiota in cancer treatment and give specific examples of bacteria that show anticancer effect when administered as a monotherapy or as an adjuvant agent for immunotherapy. We will also list ongoing clinical trials testing the anticancer effect of commensal bacteria.

키워드

과제정보

We thank Tirhas Niguse Gebre for proofreading this manuscript. This work was supported by grants from the National Research Foundation of Korea (2017M3A9F3047085, 2020R1A2C2011307) and the 2020 Joint Research Project Grant of Institutes of Science and Technology.

참고문헌

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249. https://doi.org/10.3322/caac.21660
  2. DeVita VT Jr, Rosenberg SA. Two hundred years of cancer research. N Engl J Med 2012;366:2207-2214. https://doi.org/10.1056/NEJMra1204479
  3. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8:59-73. https://doi.org/10.1038/nri2216
  4. Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 2011;3:623-636. https://doi.org/10.1002/emmm.201100176
  5. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020;20:651-668. https://doi.org/10.1038/s41577-020-0306-5
  6. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264. https://doi.org/10.1038/nrc3239
  7. Jeong S, Park SH. Co-stimulatory receptors in cancers and their implications for cancer immunotherapy. Immune Netw 2020;20:e3.
  8. Twomey JD, Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J 2021;23:39.
  9. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 2021;16:223-249. https://doi.org/10.1146/annurev-pathol-042020-042741
  10. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-1639. https://doi.org/10.1056/NEJMoa1507643
  11. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-1813. https://doi.org/10.1056/NEJMoa1510665
  12. Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019;20:1239-1251. https://doi.org/10.1016/S1470-2045(19)30388-2
  13. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454. https://doi.org/10.1056/NEJMoa1200690
  14. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019;19:133-150. https://doi.org/10.1038/s41568-019-0116-x
  15. Rousseau B, Foote MB, Maron SB, Diplas BH, Lu S, Argiles G, Cercek A, Diaz LA Jr. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N Engl J Med 2021;384:1168-1170. https://doi.org/10.1056/NEJMc2031965
  16. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 2018;33:570-580. https://doi.org/10.1016/j.ccell.2018.03.015
  17. Kramer MG, Masner M, Ferreira FA, Hoffman RM. Bacterial therapy of cancer: Promises, limitations, and insights for future directions. Front Microbiol 2018;9:16.
  18. Sedighi M, Zahedi Bialvaei A, Hamblin MR, Ohadi E, Asadi A, Halajzadeh M, Lohrasbi V, Mohammadzadeh N, Amiriani T, Krutova M, et al. Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Med 2019;8:3167-3181. https://doi.org/10.1002/cam4.2148
  19. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med 2018;24:392-400. https://doi.org/10.1038/nm.4517
  20. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004;431:931-945. https://doi.org/10.1038/nature03001
  21. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804-810. https://doi.org/10.1038/nature06244
  22. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev 2012;70 Suppl 1:S38-S44. https://doi.org/10.1111/j.1753-4887.2012.00493.x
  23. Underhill DM, Gordon S, Imhof BA, Nunez G, Bousso P. Elie Metchnikoff (1845-1916): celebrating 100 years of cellular immunology and beyond. Nat Rev Immunol 2016;16:651-656. https://doi.org/10.1038/nri.2016.89
  24. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010;10:159-169. https://doi.org/10.1038/nri2710
  25. Lo BC, Chen GY, Nunez G, Caruso R. Gut microbiota and systemic immunity in health and disease. Int Immunol 2021;33:197-209. https://doi.org/10.1093/intimm/dxaa079
  26. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005;122:107-118. https://doi.org/10.1016/j.cell.2005.05.007
  27. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014;157:121-141. https://doi.org/10.1016/j.cell.2014.03.011
  28. Price AE, Shamardani K, Lugo KA, Deguine J, Roberts AW, Lee BL, Barton GM. A map of toll-like receptor expression in the intestinal epithelium reveals distinct spatial, cell type-specific, and temporal patterns. Immunity 2018;49:560-575.e6. https://doi.org/10.1016/j.immuni.2018.07.016
  29. Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 2013;14:676-684. https://doi.org/10.1038/ni.2640
  30. Jacobson A, Yang D, Vella M, Chiu IM. The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunol 2021;14:555-565. https://doi.org/10.1038/s41385-020-00368-1
  31. Morton AM, Sefik E, Upadhyay R, Weissleder R, Benoist C, Mathis D. Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. Proc Natl Acad Sci U S A 2014;111:6696-6701. https://doi.org/10.1073/pnas.1405634111
  32. Khosravi A, Yanez A, Price JG, Chow A, Merad M, Goodridge HS, Mazmanian SK. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 2014;15:374-381. https://doi.org/10.1016/j.chom.2014.02.006
  33. Lee S, Kim H, You G, Kim YM, Lee S, Le VH, Kwon O, Im SH, Kim YM, Kim KS, et al. Bone marrow CX3CR1+ mononuclear cells relay a systemic microbiota signal to control hematopoietic progenitors in mice. Blood 2019;134:1312-1322.
  34. 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;107:12204-12209. https://doi.org/10.1073/pnas.0909122107
  35. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011;332:974-977. https://doi.org/10.1126/science.1206095
  36. Telesford KM, Yan W, Ochoa-Reparaz J, Pant A, Kircher C, Christy MA, Begum-Haque S, Kasper DL, Kasper LH. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39+Foxp3+ T cells and Treg function. Gut Microbes 2015;6:234-242. https://doi.org/10.1080/19490976.2015.1056973
  37. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013;500:232-236. https://doi.org/10.1038/nature12331
  38. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011;331:337-341. https://doi.org/10.1126/science.1198469
  39. Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 2015;163:367-380. https://doi.org/10.1016/j.cell.2015.08.058
  40. Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, Laufer TM, Ignatowicz L, Ivanov II. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014;40:594-607. https://doi.org/10.1016/j.immuni.2014.03.005
  41. Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, Lee JY, Ziel JW, Miraldi ER, Domingos AI, et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid a to promote local effector Th17 responses. Cell 2015;163:381-393. https://doi.org/10.1016/j.cell.2015.08.061
  42. Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, et al. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science 2019;363:eaat4042.
  43. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485-498. https://doi.org/10.1016/j.cell.2009.09.033
  44. Ansaldo E, Slayden LC, Ching KL, Koch MA, Wolf NK, Plichta DR, Brown EM, Graham DB, Xavier RJ, Moon JJ, et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 2019;364:1179-1184. https://doi.org/10.1126/science.aaw7479
  45. Chai JN, Peng Y, Rengarajan S, Solomon BD, Ai TL, Shen Z, Perry JS, Knoop KA, Tanoue T, Narushima S, et al. Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci Immunol 2017;2:eaal5068.
  46. Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R, Littman DR. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 2018;554:373-377. https://doi.org/10.1038/nature25500
  47. Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T, et al. Ectopic colonization of oral bacteria in the intestine drives Th1 cell induction and inflammation. Science 2017;358:359-365.  https://doi.org/10.1126/science.aan4526
  48. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569-573. https://doi.org/10.1126/science.1241165
  49. Haghikia A, Jorg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee DH, May C, Wilck N, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 2015;43:817-829. https://doi.org/10.1016/j.immuni.2015.09.007
  50. Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, Ha S, Nelson BN, Kelly SP, Wu L, et al. Bile acid metabolites control Th17 and Treg cell differentiation. Nature 2019;576:143-148. https://doi.org/10.1038/s41586-019-1785-z
  51. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, et al. ATP drives lamina propria Th17 cell differentiation. Nature 2008;455:808-812. https://doi.org/10.1038/nature07240
  52. Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W, Sugiura Y, Narushima S, Vlamakis H, Motoo I, Sugita K, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 2019;565:600-605. https://doi.org/10.1038/s41586-019-0878-z
  53. Luu M, Weigand K, Wedi F, Breidenbend C, Leister H, Pautz S, Adhikary T, Visekruna A. Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate. Sci Rep 2018;8:14430.
  54. Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D, Hochheiser K, Whitney PG, Fernandez-Ruiz D, Dahling S, Kastenmuller W, et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 2019;51:285-297.e5. https://doi.org/10.1016/j.immuni.2019.06.002
  55. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12:4077.
  56. Dobosz P, Dzieciatkowski T. The intriguing history of cancer immunotherapy. Front Immunol 2019;10:2965.
  57. Oiseth SJ, Aziz MS. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat 2017;3:250-261. https://doi.org/10.20517/2394-4722.2017.41
  58. Alexandroff AB, Jackson AM, O'Donnell MA, James K. BCG immunotherapy of bladder cancer: 20 years on. Lancet 1999;353:1689-1694. https://doi.org/10.1016/S0140-6736(98)07422-4
  59. Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter D, Kitchener H, Castellsague X, Teixeira JC, Skinner SR, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;374:301-314. https://doi.org/10.1016/S0140-6736(09)61248-4
  60. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342:971-976. https://doi.org/10.1126/science.1240537
  61. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013;342:967-970. https://doi.org/10.1126/science.1240527
  62. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350:1079-1084. https://doi.org/10.1126/science.aad1329
  63. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350:1084-1089.  https://doi.org/10.1126/science.aac4255
  64. Routy B, Le Chatelier E, Derosa L, Duong CP, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-97. https://doi.org/10.1126/science.aan3706
  65. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97-103. https://doi.org/10.1126/science.aan4236
  66. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104-108. https://doi.org/10.1126/science.aao3290
  67. Picard C, Fioramonti J, Francois A, Robinson T, Neant F, Matuchansky C. Review article: bifidobacteria as probiotic agents -- physiological effects and clinical benefits. Aliment Pharmacol Ther 2005;22:495-512. https://doi.org/10.1111/j.1365-2036.2005.02615.x
  68. Freitas AC, Hill JE. Bifidobacteria isolated from vaginal and gut microbiomes are indistinguishable by comparative genomics. PLoS One 2018;13:e0196290.
  69. O'Callaghan A, van Sinderen D. Bifidobacteria and their role as members of the human gut microbiota. Front Microbiol 2016;7:925.
  70. Lee SH, Cho SY, Yoon Y, Park C, Sohn J, Jeong JJ, Jeon BN, Jang M, An C, Lee S, et al. Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice. Nat Microbiol 2021;6:277-288. https://doi.org/10.1038/s41564-020-00831-6
  71. Shi Y, Zheng W, Yang K, Harris KG, Ni K, Xue L, Lin W, Chang EB, Weichselbaum RR, Fu YX. Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med 2020;217:e20192282.
  72. Mager LF, Burkhard R, Pett N, Cooke NC, Brown K, Ramay H, Paik S, Stagg J, Groves RA, Gallo M, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 2020;369:1481-1489. https://doi.org/10.1126/science.abc3421
  73. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 2004;54:1469-1476. https://doi.org/10.1099/ijs.0.02873-0
  74. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066-9071. https://doi.org/10.1073/pnas.1219451110
  75. Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog 2017;106:171-181. https://doi.org/10.1016/j.micpath.2016.02.005
  76. Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol 2007;73:7767-7770. https://doi.org/10.1128/AEM.01477-07
  77. Zheng Y, Wang T, Tu X, Huang Y, Zhang H, Tan D, Jiang W, Cai S, Zhao P, Song R, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer 2019;7:193.
  78. Fisher K, Phillips C. The ecology, epidemiology and virulence of Enterococcus. Microbiology (Reading) 2009;155:1749-1757. https://doi.org/10.1099/mic.0.026385-0
  79. Hanchi H, Mottawea W, Sebei K, Hammami R. The genus enterococcus: between probiotic potential and safety concerns-an update. Front Microbiol 2018;9:1791.
  80. Daillere R, Vetizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V, Duong CP, Flament C, Lepage P, Roberti MP, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 2016;45:931-943.  https://doi.org/10.1016/j.immuni.2016.09.009
  81. Griffin ME, Espinosa J, Becker JL, Luo JD, Carroll TS, Jha JK, Fanger GR, Hang HC. Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy. Science 2021;373:1040-1046. https://doi.org/10.1126/science.abc9113
  82. Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev 2007;20:593-621. https://doi.org/10.1128/CMR.00008-07
  83. Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, Koh AY. 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;19:848-855. https://doi.org/10.1016/j.neo.2017.08.004
  84. Martin R, Miquel S, Benevides L, Bridonneau C, Robert V, Hudault S, Chain F, Berteau O, Azevedo V, Chatel JM, et al. Functional characterization of novel Faecalibacterium prausnitzii strains isolated from healthy volunteers: a step forward in the use of F. prausnitzii as a next-generation probiotic. Front Microbiol 2017;8:1226.
  85. Coutzac C, Jouniaux JM, Paci A, Schmidt J, Mallardo D, Seck A, Asvatourian V, Cassard L, Saulnier P, Lacroix L, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun 2020;11:2168.
  86. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017;28:1368-1379. https://doi.org/10.1093/annonc/mdx108
  87. Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021;371:595-602. https://doi.org/10.1126/science.abf3363
  88. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, Adler K, Dick-Necula D, Raskin S, Bloch N, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021;371:602-609.
  89. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MR, Huntley MH, Turbett S, Chung RT, Chen YB, Hohmann EL. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med 2019;381:2043-2050. https://doi.org/10.1056/NEJMoa1910437