The intimate relationship between gut microbiota and cancer immunotherapy

Arielle Elkrief, Lisa Derosa, Laurence Zitvogel, Guido Kroemer, Bertrand Routy, Arielle Elkrief, Lisa Derosa, Laurence Zitvogel, Guido Kroemer, Bertrand Routy

Abstract

Immunotherapy is widely used to treat a large variety of malignancies and has revolutionized the therapeutic approach to cancer. Major efforts are ongoing to identify biomarkers that predict response to immunotherapy as well as new strategies to improve ICI efficacy and clinical outcomes. Studies have shown that the gut microbiome determines the extent to which ICIs may invigorate the anticancer immune response. Here, the authors review recent studies that have described the effects of the gut microbiota on the efficacy of CTLA-4 and PD-1 inhibitors and outline potential future clinical directions of these findings.

Keywords: Gut microbiota; cancer; fecal transplantation; host pathogen interactions; immunotherapy; oncology; profiling gut microbiome.

Figures

Figure 1.
Figure 1.
Link between microbiota diversity and composition with immune checkpoint inhibitors clinical response. Upper panel: Patients that did not respond to ICI have a lower microbiota diversity. Prescription of antibiotics (in favour of a lower microbiota diversity) prior to commence ICI was associated with a poorer clinical response.Middle panel: Bacteria overrepresented in deleterious microbiota associated with non-responders, and bacteria enriched in responders with favourable microbiota and their respective mechanisms influencing the anti-cancer immune responseLower panel: Strategies to manipulate the gut microbiota and transform an unfavourable to favourable microbiota to enhance ICI response.

References

    1. Pardoll D. Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol. 2015;42(4):523–538. doi:10.1053/j.seminoncol.2015.05.003.
    1. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus Chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. doi:10.1056/NEJMoa1606774.
    1. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018; doi:10.1056/NEJMoa1801946.
    1. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018; doi:10.1056/NEJMoa1716078.
    1. Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–734. doi:10.1038/nrclinonc.2017.101.
    1. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–128. doi:10.1126/science.aaa1348.
    1. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van Den Heuvel MM, Ciuleanu T-E, Badin F, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–2426. doi:10.1056/NEJMoa1613493.
    1. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–235. doi:10.1038/nature14404.
    1. 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(19):1803–1813. doi:10.1056/NEJMoa1510665.
    1. Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation and cancer. Nat Immunol. 2017;18(8):843–850. doi:10.1038/ni.3754.
    1. Goubet AG, Daillere R, Routy B, Derosa L, Roberti PM, Zitvogel L. The impact of the intestinal microbiota in therapeutic responses against cancer. C R Biol. 2018; doi:10.1016/j.crvi.2018.03.004.
    1. Zitvogel L, Daillere R, Roberti MP, Routy B, Kroemer G. Anticancer effects of the microbiome and its products. Nat Rev Microbiol. 2017;15(8):465–478. doi:10.1038/nrmicro.2017.44.
    1. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre M-L, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–1089. doi:10.1126/science.aac4255.
    1. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CPM, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–1084. doi:10.1126/science.aad1329.
    1. 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(6):1368–1379. doi:10.1093/annonc/mdx108.
    1. Routy B, Le Chatelier E, Derosa L, Duong CPM, 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(6371):91–97. doi:10.1126/science.aan3706.
    1. Manichanh C, Reeder J, Gibert P, Varela E, Llopis M, Antolin M, Guigo R, Knight R, Guarner F. Reshaping the gut microbiome with bacterial transplantation and antibiotic intake. Genome Res. 2010;20(10):1411–1419. doi:10.1101/gr.107987.110.
    1. 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(6371):97–103. doi:10.1126/science.aan4236.
    1. 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. doi:10.1126/science.aao3290.
    1. 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(23):7767–7770. doi:10.1128/AEM.01477-07.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe