Skip to main content
SpringerLink
Log in

Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

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. Xu BB, He YJ, Wang WL, Zhou CF, Xie SC, Shen DY, Lmcleod H. Research progress of immune checkpoint therapy for cancer. Chin J Clin Pharm Ther (Zhongguo Lin Chuang Yao Li Xue Yu Zhi Liao Xue) 2016; 21(2): 218–234 (in Chinese)

    CAS  Google Scholar 

  2. Chen P, Lin JG, Dai YB, Zhao AY, Dai YJ, Xu TW. Progress in understanding the relationship between gut microbiota and immune checkpoint inhibitors. Chin J Clin Oncol (Zhongguo Zhong Liu Lin Chuang) 2019; 46(24): 1292–1296 (in Chinese)

    Google Scholar 

  3. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018; 50(12): 1–11

    Article  PubMed  CAS  Google Scholar 

  4. Zhao S, Gao G, Li W, Li X, Zhao C, Jiang T, Jia Y, He Y, Li A, Su C, Ren S, Chen X, Zhou C. Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer 2019; 130: 10–17

    Article  PubMed  Google Scholar 

  5. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 2019; 38(1): 255

    Article  PubMed  PubMed Central  Google Scholar 

  6. Herrera-Camacho I, Anaya-Ruiz M, Perez-Santos M, Millán-Pérez Peña L, Bandala C, Landeta G. Cancer immunotherapy using anti-TIM3/PD-1 bispecific antibody: a patent evaluation of EP3356411A1. Expert Opin Ther Pat 2019; 29(8): 587–593

    Article  CAS  PubMed  Google Scholar 

  7. Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, Dong W, Mani N, Toki M, Mejías LD, Lozano MD, Perez-Gracia JL, Velcheti V, Hellmann MD, Gainor JF, McEachern K, Jenkins D, Syrigos K, Politi K, Gettinger S, Rimm DL, Herbst RS, Melero I, Chen L, Schalper KA. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res 2019; 25(15): 4663–4673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McCarthy MW, Walsh TJ. Checkpoint inhibitors and the risk of infection. Expert Rev Precis Med Drug Dev 2017; 2(5): 287–293

    Article  Google Scholar 

  9. Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DAA. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol 2019; 42: 101305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang X, Zhang X, Li E, Zhang G, Wang X, Tang T, Bai X, Liang T. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 2020; 13(1): 83

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, Zhao H, Chen J, Chen H, Efstathiou E, Troncoso P, Allison JP, Logothetis CJ, Wistuba II, Sepulveda MA, Sun J, Wargo J, Blando J, Sharma P. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 2017; 23(5): 551–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Willingham SB, Hotson AN, Miller RA. Targeting the A2AR in cancer; early lessons from the clinic. Curr Opin Pharmacol 2020; 53: 126–133

    Article  CAS  PubMed  Google Scholar 

  13. Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, George S, Hughes BGM, Hellmann MD, Shepard DR, Rini BI, Kummar S, Weise AM, Riese MJ, Markman B, Emens LA, Mahadevan D, Luke JJ, Laport G, Brody JD, Hernandez-Aya L, Bonomi P, Goldman JW, Berim L, Renouf DJ, Goodwin RA, Munneke B, Ho PY, Hsieh J, McCaffery I, Kwei L, Willingham SB, Miller RA. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov 2020; 10(1): 40–53

    Article  CAS  PubMed  Google Scholar 

  14. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 2020; 10(3): 727–742

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 2015; 21(1): 24–33

    Article  CAS  PubMed  Google Scholar 

  16. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 2020; 37(4): 443–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang Y, Ma R, Liu F, Lee SA, Zhang L. Modulation of gut microbiota: a novel paradigm of enhancing the efficacy of programmed death-1 and programmed death ligand-1 blockade therapy. Front Immunol 2018; 9: 374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5(12): 1365–1369

    Article  CAS  PubMed  Google Scholar 

  19. Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol 2019; 12(1): 92

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, Sharpe AH, Freeman GJ, Germain RN, Nakaya HI, Xue HH, Ahmed R. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016; 537(7620): 417–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yi M, Yu S, Qin S, Liu Q, Xu H, Zhao W, Chu Q, Wu K. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol 2018; 11(1): 47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1): 98–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM. Transendocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011; 332(6029): 600–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood 2018; 131(1): 58–67

    Article  CAS  PubMed  Google Scholar 

  25. Yan CX, Zhang R, Wang NX. Immune-related adverse reactions with PD-1/PD-L1 mab. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi) 2018; 33(3): 333–336 (in Chinese)

    Google Scholar 

  26. Yang H, Zhou C, Yuan F, Guo L, Yang L, Shi Y, Zhang J. Case report: severe immune-related cholestatic hepatitis and subsequent pneumonia after pembrolizumab therapy in a geriatic patient with metastic gastric cancer. Front Med (Lausanne) 2021; 8: 719236

    Article  Google Scholar 

  27. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 2018; 118(1): 9–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Benfaremo D, Manfredi L, Luchetti MM, Gabrielli A. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: a review of the literature. Curr Drug Saf 2018; 13(3): 150–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun L, Liu Z, Zhang S. Adverse reaction and management of immune checkpoint inhibitor. J Med Postgra (Yi Xue Yan Jiu Sheng Xue Bao) 2019; 32(10): 1115–1120 (in Chinese)

    Google Scholar 

  30. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res 2015; 4(5): 560–575

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Shah R, Witt D, Asif T, Mir FF. Ipilimumab as a cause of severe pan-colitis and colonic perforation. Cureus 2017; 9(4): e1182

    PubMed  PubMed Central  Google Scholar 

  32. Karam JD, Noel N, Voisin AL, Lanoy E, Michot JM, Lambotte O. Infectious complications in patients treated with immune checkpoint inhibitors. Eur J Cancer 2020; 141: 137–142

    Article  CAS  PubMed  Google Scholar 

  33. Del Castillo M, Romero FA, Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 2016; 63(11): 1490–1493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ross JA, Komoda K, Pal S, Dickter J, Salgia R, Dadwal S. Infectious complications of immune checkpoint inhibitors in solid organ malignancies. Cancer Med 2022; 11(1): 21–27

    Article  CAS  PubMed  Google Scholar 

  35. Boegeholz J, Brueggen CS, Pauli C, Dimitriou F, Haralambieva E, Dummer R, Manz MG, Widmer CC. Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect. BMC Cancer 2020; 20(1): 300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guo M, Balaji A, Murray J, Reuss J, Steinke SM, Naidoo J. 237 Infectious complications in patients with non-small cell lung cancer treated with anti-PD (L) 1 immune checkpoint inhibitors. J Immunother Cancer 2021; 9(Suppl 2): A253

    Article  Google Scholar 

  37. Fujita K, Kim YH, Kanai O, Yoshida H, Mio T, Hirai T. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy. Respir Med 2019; 146: 66–70

    Article  PubMed  Google Scholar 

  38. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36(17): 1714–1768

    Article  CAS  PubMed  Google Scholar 

  39. Li GH, Huang HB, Yang M, Chen X, Liu ST, Zheng ZH. Guidelines for whole-course pharmaceutical care with immune checkpoint inhibitors (2019 Edition). Pharm Today (Jin Ri Yao Xue) 2020; 30(5): 289–306 (in Chinese)

    Google Scholar 

  40. Yang MX, Yuan M, Tong JD, Yan XB. Role of antibiotics in tumor development and immunotherapy. J Int Oncol (Guo Ji Zhong Liu Xue Za Zhi) 2021; 48(1): 48–51 (in Chinese)

    Google Scholar 

  41. Castello A, Rossi S, Toschi L, Lopci E. Impact of antibiotic therapy and metabolic parameters in non-small cell lung cancer patients receiving checkpoint inhibitors. J Clin Med 2021; 10(6): 1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang YH, Zhang RH. Progress in diagnosis and treatment of adverse reactions related to immune checkpoint inhibitors in advanced lung cancer. Zhejiang Med (Zhe Jiang Yi Xue) 2020; 42(12): 1227–1231 (in Chinese)

    Google Scholar 

  43. Fishman JA, Hogan JI, Maus MV. Inflammatory and infectious syndromes associated with cancer immunotherapies. Clin Infect Dis 2019; 69(6): 909–920

    Article  CAS  PubMed  Google Scholar 

  44. Huang XZ, Gao P, Song YX, Xu Y, Sun JX, Chen XW, Zhao JH, Wang ZN. Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients. OncoImmunology 2019; 8(12): e1665973

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, Brock C, Power D, Hatcher O, Falconer A, Ingle M, Brown A, Gujral D, Partridge S, Sarwar N, Gonzalez M, Bendle M, Lewanski C, Newsom-Davis T, Allara E, Bower M. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019; 5(12): 1774–1778

    Article  PubMed  PubMed Central  Google Scholar 

  46. Galli G, Triulzi T, Proto C, Signorelli D, Imbimbo M, Poggi M, Fucà G, Ganzinelli M, Vitali M, Palmieri D, Tessari A, de Braud F, Garassino MC, Colombo MP, Lo Russo G. Association between antibiotic-immunotherapy exposure ratio and outcome in metastatic non small cell lung cancer. Lung Cancer 2019; 132: 72–78

    Article  PubMed  Google Scholar 

  47. Tsikala-Vafea M, Belani N, Vieira K, Khan H, Farmakiotis D. Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Int J Infect Dis 2021; 106: 142–154

    Article  CAS  PubMed  Google Scholar 

  48. Hakozaki T, Okuma Y, Omori M, Hosomi Y. Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett 2019; 17(3): 2946–2952

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mata-Molanes JJ, Sureda González M, Valenzuela Jiménez B, Martínez Navarro EM, Brugarolas Masllorens A. Cancer immunotherapy with cytokine-induced killer cells. Target Oncol 2017; 12(3): 289–299

    Article  PubMed  Google Scholar 

  50. Sethi V, Kurtom S, Tarique M, Lavania S, Malchiodi Z, Hellmund L, Zhang L, Sharma U, Giri B, Garg B, Ferrantella A, Vickers SM, Banerjee S, Dawra R, Roy S, Ramakrishnan S, Saluja A, Dudeja V. Gut microbiota promotes tumor growth in mice by modulating immune response. Gastroenterology 2018; 155(1): 33–37.e6

    Article  CAS  PubMed  Google Scholar 

  51. Wei MY, Shi S, Liang C, Meng QC, Hua J, Zhang YY, Liu J, Zhang B, Xu J, Yu XJ. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer 2019; 18(1): 97

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, Bushman FD, Artis D. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol 2010; 3(2): 148–158

    Article  CAS  PubMed  Google Scholar 

  53. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97

    Article  CAS  PubMed  Google Scholar 

  54. Ahmed J, Kumar A, Parikh K, Anwar A, Knoll BM, Puccio C, Chun H, Fanucchi M, Lim SH. Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors. OncoImmunology 2018; 7(11): e1507670

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yin Y, Qiu XY, Zhao ZG, Zhang YH. Discussion on the effect of antibiotics on the effectiveness of PD-1/PD-L1 antibody immunotherapy. Pract Pharm Clin Remedies (Shi Yong Yao Wu Yu Lin Chuang) 2021; 24(3): 267–269 (in Chinese)

    Google Scholar 

  56. Spakowicz D, Hoyd R, Muniak M, Husain M, Bassett JS, Wang L, Tinoco G, Patel SH, Burkart J, Miah A, Li M, Johns A, Grogan M, Carbone DP, Verschraegen CF, Kendra KL, Otterson GA, Li L, Presley CJ, Owen DH. Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications. BMC Cancer 2020; 20(1): 383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, Long N, Plodkowski AJ, Arbour KC, Chaft JE, Rouche JA, Zitvogel L, Zalcman G, Albiges L, Escudier B, Routy B. 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): 1437–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schett A, Rothschild SI, Curioni-Fontecedro A, Krähenbühl S, Früh M, Schmid S, Driessen C, Joerger M. Predictive impact of antibiotics in patients with advanced non small-cell lung cancer receiving immune checkpoint inhibitors: antibiotics immune checkpoint inhibitors in advanced NSCLC. Cancer Chemother Pharmacol 2020; 85(1): 121–131

    Article  CAS  PubMed  Google Scholar 

  59. Lange K, Buerger M, Stallmach A, Bruns T. Effects of antibiotics on gut microbiota. Dig Dis 2016; 34(3): 260–268

    Article  PubMed  Google Scholar 

  60. Jakobsson HE, Jernberg C, Andersson AF, Sjölund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 2010; 5(3): e9836

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Yu Y, Zheng P, Gao L, Li H, Tao P, Wang D, Ding F, Shi Q, Chen H. Effects of antibiotic use on outcomes in cancer patients treated using immune checkpoint inhibitors: a systematic review and meta-analysis. J Immunother 2021; 44(2): 76–85

    Article  CAS  PubMed  Google Scholar 

  62. Iglesias-Santamaría A. Impact of antibiotic use and other concomitant medications on the efficacy of immune checkpoint inhibitors in patients with advanced cancer. Clin Transl Oncol 2020; 22(9): 1481–1490

    Article  PubMed  CAS  Google Scholar 

  63. Tinsley N, Zhou C, Tan G, Rack S, Lorigan P, Blackhall F, Krebs M, Carter L, Thistlethwaite F, Graham D, Cook N. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist 2020; 25(1): 55–63

    Article  CAS  PubMed  Google Scholar 

  64. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev 2012; 70(Suppl 1): S38–S44

    Article  PubMed  Google Scholar 

  65. Berg G, Rybakova D, Fischer D, Cernava T, Vergès MC, Charles T, Chen X, Cocolin L, Eversole K, Corral GH, Kazou M, Kinkel L, Lange L, Lima N, Loy A, Macklin JA, Maguin E, Mauchline T, McClure R, Mitter B, Ryan M, Sarand I, Smidt H, Schelkle B, Roume H, Kiran GS, Selvin J, Souza RSC, van Overbeek L, Singh BK, Wagner M, Walsh A, Sessitsch A, Schloter M. Microbiome definition re-visited: old concepts and new challenges. Microbiome 2020; 8(1): 103

    Article  PubMed  PubMed Central  Google Scholar 

  66. Velikova T, Krastev B, Lozenov S, Gencheva R, Peshevska-Sekulovska M, Nikolaev G, Peruhova M. Antibiotic-related changes in microbiome: the hidden villain behind colorectal carcinoma immunotherapy failure. Int J Mol Sci 2021; 22(4): 1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 2017; 14(6): 356–365

    Article  CAS  PubMed  Google Scholar 

  68. Zhang BC, Peng M, Song QB. Relationship between gut microbiome and efficacy of immunotherapy. J Chin Oncol (Zhong Liu Xue Za Zhi) 2018; 24(11): 1056–1059 (in Chinese)

    Google Scholar 

  69. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Swami U, Zakharia Y, Zhang J. Understanding microbiome effect on immune checkpoint inhibition in lung cancer: placing the puzzle pieces together. J Immunother 2018; 41(8): 359–360

    Article  PubMed  Google Scholar 

  71. Francino MP. Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front Microbiol 2016; 6: 1543

    Article  PubMed  PubMed Central  Google Scholar 

  72. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA 2011; 108(Suppl 1): 4554–4561

    Article  CAS  PubMed  Google Scholar 

  73. Yoon MY, Yoon SS. Disruption of the gut ecosystem by antibiotics. Yonsei Med J 2018; 59(1): 4–12

    Article  CAS  PubMed  Google Scholar 

  74. Pinato DJ, Gramenitskaya D, Altmann DM, Boyton RJ, Mullish BH, Marchesi JR, Bower M. Antibiotic therapy and outcome from immune-checkpoint inhibitors. J Immunother Cancer 2019; 7(1): 287

    Article  PubMed  PubMed Central  Google Scholar 

  75. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079–1084

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, No D, Gobourne A, Littmann E, Huttenhower C, Pamer EG, Wolchok JD. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 2016; 7(1): 10391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, Mohan N, Aykut B, Usyk M, Torres LE, Werba G, Zhang K, Guo Y, Li Q, Akkad N, Lall S, Wadowski B, Gutierrez J, Kochen Rossi JA, Herzog JW, Diskin B, Torres-Hernandez A, Leinwand J, Wang W, Taunk PS, Savadkar S, Janal M, Saxena A, Li X, Cohen D, Sartor RB, Saxena D, Miller G. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 2018; 8(4): 403–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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(6371): 104–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Daillère R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V, Duong CPM, Flament C, Lepage P, Roberti MP, Routy B, Jacquelot N, Apetoh L, Becharef S, Rusakiewicz S, Langella P, Sokol H, Kroemer G, Enot D, Roux A, Eggermont A, Tartour E, Johannes L, Woerther PL, Chachaty E, Soria JC, Golden E, Formenti S, Plebanski M, Madondo M, Rosenstiel P, Raoult D, Cattoir V, Boneca IG, Chamaillard M, Zitvogel L. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 2016; 45(4): 931–943

    Article  PubMed  CAS  Google Scholar 

  80. Derosa L, Routy B, Fidelle M, Iebba V, Alla L, Pasolli E, Segata N, Desnoyer A, Pietrantonio F, Ferrere G, Fahrner JE, Le Chatellier E, Pons N, Galleron N, Roume H, Duong CPM, Mondragón L, Iribarren K, Bonvalet M, Terrisse S, Rauber C, Goubet AG, Daillère R, Lemaitre F, Reni A, Casu B, Alou MT, Alves Costa Silva C, Raoult D, Fizazi K, Escudier B, Kroemer G, Albiges L, Zitvogel L. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur Urol 2020; 78(2): 195–206

    Article  CAS  PubMed  Google Scholar 

  81. Hamm AK, Weir TL. Editorial on “Cancer and the microbiota” published in Science. Ann Transl Med 2015; 3(13): 175

    PubMed  PubMed Central  Google Scholar 

  82. Wind TT, Gacesa R, Vich Vila A, de Haan JJ, Jalving M, Weersma RK, Hospers GAP. Gut microbial species and metabolic pathways associated with response to treatment with immune checkpoint inhibitors in metastatic melanoma. Melanoma Res 2020; 30(3): 235–246

    Article  CAS  PubMed  Google Scholar 

  83. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371): 97–103

    Article  CAS  PubMed  Google Scholar 

  84. Rezasoltani S, Yadegar A, Asadzadeh Aghdaei H, Reza Zali M. Modulatory effects of gut microbiome in cancer immunotherapy: a novel paradigm for blockade of immune checkpoint inhibitors. Cancer Med 2021; 10(3): 1141–1154

    Article  CAS  PubMed  Google Scholar 

  85. Liu X, Chen Y, Zhang S, Dong L. Gut microbiota-mediated immunomodulation in tumor. J Exp Clin Cancer Res 2021; 40(1): 221

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gong J, Chehrazi-Raffle A, Placencio-Hickok V, Guan M, Hendifar A, Salgia R. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin Transl Med 2019; 8(1): 9

    Article  PubMed  PubMed Central  Google Scholar 

  87. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, Vaysse T, Marthey L, Eggermont A, Asvatourian V, Lanoy E, Mateus C, Robert C, Carbonnel F. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28(6): 1368–1379

    Article  CAS  PubMed  Google Scholar 

  88. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 2010; 107(27): 12204–12209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S, Chung L, Finard BB, Wu X, Fathi P, Ganguly S, Fu J, Pardoll DM, Sears CL, Housseau F. The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis. Mucosal Immunol 2017; 10(2): 421–433

    Article  CAS  PubMed  Google Scholar 

  90. 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(6145): 569–573

    Article  CAS  PubMed  Google Scholar 

  91. Xu X, Lv J, Guo F, Li J, Jia Y, Jiang D, Wang N, Zhang C, Kong L, Liu Y, Zhang Y, Lv J, Li Z. Gut microbiome influences the efficacy of PD-1 antibody immunotherapy on MSS-type colorectal cancer via metabolic pathway. Front Microbiol 2020; 11: 814

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liu J, Gao Y, Wang X, Qian Z, Chen J, Huang Y, Meng Z, Lu X, Deng G, Liu F, Zhang Z, Li H, Zheng X. Culture-positive spontaneous ascitic infection in patients with acute decompensated cirrhosis: multidrug-resistant pathogens and antibiotic strategies. Yonsei Med J 2020; 61(2): 145–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee EH, Kim S, Choi MS, Yang H, Park SM, Oh HA, Moon KS, Han JS, Kim YB, Yoon S, Oh JH. Gene networking in colistin-induced nephrotoxicity reveals an adverse outcome pathway triggered by proteotoxic stress. Int J Mol Med 2019; 43(3): 1343–1355

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Imdad A, Nicholson MR, Tanner-Smith EE, Zackular JP, Gomez-Duarte OG, Beaulieu DB, Acra S. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2018; 11: CD012774

    PubMed  Google Scholar 

  95. Kamada N, Seo SU, Chen GY, Núñez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 2013; 13(5): 321–335

    Article  CAS  PubMed  Google Scholar 

  96. Pickard JM, Zeng MY, Caruso R, Núñez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev 2017; 279(1): 70–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Schwartz DJ, Rebeck ON, Dantas G. Complex interactions between the microbiome and cancer immune therapy. Crit Rev Clin Lab Sci 2019; 56(8): 567–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen D, Wu J, Jin D, Wang B, Cao H. Fecal microbiota transplantation in cancer management: current status and perspectives. Int J Cancer 2019; 145(8): 2021–2031

    Article  CAS  PubMed  Google Scholar 

  99. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, Adler K, Dick-Necula D, Raskin S, Bloch N, Rotin D, Anafi L, Avivi C, Melnichenko J, Steinberg-Silman Y, Mamtani R, Harati H, Asher N, Shapira-Frommer R, Brosh-Nissimov T, Eshet Y, Ben-Simon S, Ziv O, Khan MAW, Amit M, Ajami NJ, Barshack I, Schachter J, Wargo JA, Koren O, Markel G, Boursi B. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021; 371(6529): 602–609

    Article  CAS  PubMed  Google Scholar 

  100. Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, Zidi B, Zhang S, Badger JH, Vetizou M, Cole AM, Fernandes MR, Prescott S, Costa RGF, Balaji AK, Morgun A, Vujkovic-Cvijin I, Wang H, Borhani AA, Schwartz MB, Dubner HM, Ernst SJ, Rose A, Najjar YG, Belkaid Y, Kirkwood JM, Trinchieri G, Zarour HM. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021; 371(6529): 595–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis 2015; 60(Suppl 2): S129–S134

    Article  PubMed  PubMed Central  Google Scholar 

  102. Pandey KR, Naik SR, Vakil BV. Probiotics, prebiotics and synbiotics—a review. J Food Sci Technol 2015; 52(12): 7577–7587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995; 125(6): 1401–1412

    Article  CAS  PubMed  Google Scholar 

  104. Hu Y, Le Leu RK, Christophersen CT, Somashekar R, Conlon MA, Meng XQ, Winter JM, Woodman RJ, McKinnon R, Young GP. Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats. Carcinogenesis 2016; 37(4): 366–375

    Article  CAS  PubMed  Google Scholar 

  105. Li W, Deng Y, Chu Q, Zhang P. Gut microbiome and cancer immunotherapy. Cancer Lett 2019; 447: 41–47

    Article  CAS  PubMed  Google Scholar 

  106. Botticelli A, Zizzari I, Mazzuca F, Ascierto PA, Putignani L, Marchetti L, Napoletano C, Nuti M, Marchetti P. Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment. Oncotarget 2017; 8(5): 8890–8899

    Article  PubMed  Google Scholar 

  107. Li Y, Zhao R, Cheng K, Zhang K, Wang Y, Zhang Y, Li Y, Liu G, Xu J, Xu J, Anderson GJ, Shi J, Ren L, Zhao X, Nie G. Bacterial outer membrane vesicles presenting programmed death 1 for improved cancer immunotherapy via immune activation and checkpoint inhibition. ACS Nano 2020; 14(12): 16698–16711

    Article  CAS  Google Scholar 

  108. Huang J, Liu D, Wang Y, Liu L, Li J, Yuan J, Jiang Z, Jiang Z, Hsiao WW, Liu H, Khan I, Xie Y, Wu J, Xie Y, Zhang Y, Fu Y, Liao J, Wang W, Lai H, Shi A, Cai J, Luo L, Li R, Yao X, Fan X, Wu Q, Liu Z, Yan P, Lu J, Yang M, Wang L, Cao Y, Wei H, Leung EL. Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut 2022; 71(4): 734–745

    Article  CAS  PubMed  Google Scholar 

  109. Lv J, Jia Y, Li J, Kuai W, Li Y, Guo F, Xu X, Zhao Z, Lv J, Li Z. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis 2019; 10(6): 415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Zhen H, Qian X, Fu X, Chen Z, Zhang A, Shi L. Regulation of Shaoyao Ruangan mixture on intestinal flora in mice with primary liver cancer. Integr Cancer Ther 2019; 18: 1534735419843178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. McFadden RM, Larmonier CB, Shehab KW, Midura-Kiela M, Ramalingam R, Harrison CA, Besselsen DG, Chase JH, Caporaso JG, Jobin C, Ghishan FK, Kiela PR. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflamm Bowel Dis 2015; 21(11): 2483–2494

    Article  PubMed  Google Scholar 

  112. Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 2014; 7(1): 17–44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Mehta RS, Nishihara R, Cao Y, Song M, Mima K, Qian ZR, Nowak JA, Kosumi K, Hamada T, Masugi Y, Bullman S, Drew DA, Kostic AD, Fung TT, Garrett WS, Huttenhower C, Wu K, Meyerhardt JA, Zhang X, Willett WC, Giovannucci EL, Fuchs CS, Chan AT, Ogino S. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017; 3(7): 921–927

    Article  PubMed  PubMed Central  Google Scholar 

  114. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107(33): 14691–14696

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wei W, Sun W, Yu S, Yang Y, Ai L. Butyrate production from high-fiber diet protects against lymphoma tumor. Leuk Lymphoma 2016; 57(10): 2401–2408

    Article  CAS  PubMed  Google Scholar 

  116. Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 2017; 36(42): 5829–5839

    Article  CAS  PubMed  Google Scholar 

  117. Seth P, Csizmadia E, Hedblom A, Vuerich M, Xie H, Li M, Longhi MS, Wegiel B. Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity. Cancer Res 2017; 77(13): 3632–3643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Poroyko VA, Carreras A, Khalyfa A, Khalyfa AA, Leone V, Peris E, Almendros I, Gileles-Hillel A, Qiao Z, Hubert N, Farré R, Chang EB, Gozal D. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep 2016; 6(1): 35405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 2017; 357(6354): 912–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wang J, Yang HR, Wang DJ, Wang XX. Association between the gut microbiota and patient responses to cancer immune checkpoint inhibitors. Oncol Lett 2020; 20(6): 342

    PubMed  PubMed Central  Google Scholar 

  121. Lee KA, Shaw HM, Bataille V, Nathan P, Spector TD. Role of the gut microbiome for cancer patients receiving immunotherapy: dietary and treatment implications. Eur J Cancer 2020; 138: 149–155

    Article  CAS  PubMed  Google Scholar 

  122. Zhang J, Dai Z, Yan C, Zhang W, Wang D, Tang D. A new biological triangle in cancer: intestinal microbiota, immune checkpoint inhibitors and antibiotics. Clin Transl Oncol 2021; 23(12): 2415–2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Patel P, Poudel A, Kafle S, Thapa Magar M, Cancarevic I. Influence of microbiome and antibiotics on the efficacy of immune checkpoint inhibitors. Cureus 2021; 13(8): e16829

    PubMed  PubMed Central  Google Scholar 

  124. Qu J, Jiang M, Wang L, Zhao D, Qin K, Wang Y, Tao J, Zhang X. Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC. Biomed Pharmacother 2020; 127: 109996

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2020L03) and Beijing Municipal Science & Technology Commission (No. Z1811000-01618003).

Author information

Author notes

  1. These authors have contributed equally to this work.

Authors and Affiliations

  1. Pharmacy Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yingying Li, Shiyuan Wang, Mengmeng Lin, Chunying Hou, Chunyu Li & Guohui Li

Authors
  1. Yingying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengmeng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chunying Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunyu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guohui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chunyu Li or Guohui Li.

Additional information

Compliance with ethics guidelines

Yingying Li, Shiyuan Wang, Mengmeng Lin, Chunying Hou, Chunyu Li, and Guohui Li declare no conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Wang, S., Lin, M. et al. Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy. Front. Med. 16, 307–321 (2022). https://doi.org/10.1007/s11684-022-0927-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-022-0927-0

Keywords

Search

Navigation