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Mikrobiom und Immuntherapien bei Tumorerkrankungen

  • E. HollerEmail author
  • D. Weber
  • D. Heudobler
  • D. Wolff
  • W. Herr
Schwerpunkt
  • 16 Downloads

Zusammenfassung

Hintergrund

Das intestinale Mikrobiom ist in den letzten 5 Jahren als ein wesentlicher Modulator der intestinalen und systemischen Immunregulation beschrieben worden.

Material und Methoden

In der vorliegenden Arbeit werden deshalb die experimentelle und klinische Evidenz in aktueller Literatur und eigenen Arbeiten für eine Modulation der Tumorimmuntherapie durch das Mikrobiom zusammengefasst.

Ergebnisse und Schlussfolgerung

Vor allem in der allogenen Stammzelltransplantation, aber auch bei der Gabe von Checkpointinhibitoren sind immunologische Nebenwirkungen erheblich mikrobiomabhängig. Auch die Tumorkontrolle und damit das langfristige Überleben können durch Mikrobiomverschiebungen stark beeinflusst werden. Eine exakte Entschlüsselung der zugrunde liegenden Mechanismen auf Stamm- und Metabolitenebene ist erforderlich, um in Zukunft gezielt durch Veränderungen des Mikrobioms die Wirkung von Immuntherapeutika zu verbessern und ihre Nebenwirkungen effektiver kontrollieren zu können.

Schlüsselwörter

Dysbiose Immunregulation Immunkontrolle Transplantat-gegen-Wirt-Erkrankung Immunsystemerkrankungen 

Microbiota and immuno-oncology—a new alliance

Abstract

Background

In the last 5 years, the intestinal microbiome has been described as a major driver and modulator of intestinal but also systemic immunoregulation.

Materials and methods

Based on the literature and our own experience, we summarize the current knowledge of the role of the microbiome in various types of immunotherapy for the treatment of hematological and solid malignancies.

Results and conclusions

Immunological side effects of allogeneic stem cell transplantation but also treatment of solid cancers with checkpoint inhibitors are strongly controlled by intestinal microbiota. Furthermore, recent evidence indicates the contribution of intact microbiota and microbiota-dependent immunoregulation to efficacy and control of tumor growth by checkpoint inhibitors and cellular immunotherapy. Further research addressing microbiota strain-specific mechanisms and metabolites is needed to utilize these interactions for optimization of immunotherapy of cancer.

Keywords

Dysbiosis Immunomodulation Cell cycle checkpoints Graft-versus-host disease Immune system diseases 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

E. Holler, D. Weber, D. Heudobler, D. Wolff und W. Herr geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Männel DN, Rosenstreich DL, Mergenhagen SE (1979) Mechanism of lipopolysaccharide-induced tumor necrosis: Requirement for lipopolysaccharide-sensitive lymphoreticular cells. Infect Immun 24(2):573–576PubMedPubMedCentralGoogle Scholar
  2. 2.
    Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A (1985) Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316(6028):552–554CrossRefGoogle Scholar
  3. 3.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022CrossRefGoogle Scholar
  4. 4.
    Honda K, Littman DR (2016) The microbiota in adaptive immune homeostasis and disease. Nature 535(7610):75–84CrossRefGoogle Scholar
  5. 5.
    Iida N, Dzutsev A, Stewart CA et al (2013) Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:96770CrossRefGoogle Scholar
  6. 6.
    Viaud S, Saccheri F, Mignot G et al (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–973CrossRefGoogle Scholar
  7. 7.
    Pflug N, Kluth S, Vehreschild JJ, Bahlo J, Tacke D, Biehl L, Eichhorst B, Fischer K, Cramer P, Fink AM, von Bergwelt-Baildon M, Stilgenbauer S, Hallek M, Cornely OA, Vehreschild MJ (2016) Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota. Oncoimmunology 5(6):e1150399CrossRefGoogle Scholar
  8. 8.
    Peled JU, Jenq RR, Holler E, van den Brink MR (2016) Role of gut flora after bone marrow transplantation. Nat Microbiol 1(4):16036CrossRefGoogle Scholar
  9. 9.
    Andermann TM, Peled JU, Ho C, Reddy P, Riches M, Storb R, Teshima T, van den Brink MRM, Alousi A, Balderman S, Chiusolo P, Clark WB, Holler E, Howard A, Kean LS, Koh AY, McCarthy PL, McCarty JM, Mohty M, Nakamura R, Rezvani K, Segal BH, Shaw BE, Shpall EJ, Sung AD, Weber D, Whangbo J, Wingard JR, Wood WA, Perales MA, Jenq RR, Bhatt AS, Blood and Marrow Transplant Clinical Trials Network (2018) The microbiome and hematopoietic cell transplantation: Past, present, and future. Biol Blood Marrow Transplant 24(7):1322–1340CrossRefGoogle Scholar
  10. 10.
    DeFilipp Z, Hohmann E, Jenq RR, Chen YB (2019) Fecal microbiota transplantation: Restoring the injured microbiome after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 25(1):e17–e22.  https://doi.org/10.1016/j.bbmt.2018.10.022 CrossRefPubMedGoogle Scholar
  11. 11.
    Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E (2017) Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 23(5):845–852CrossRefGoogle Scholar
  12. 12.
    Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, Oravecz-Wilson K, Wu SR, Sun Y, Rossi C, Fujiwara H, Byun J, Shono Y, Lindemans C, Calafiore M, Schmidt TM, Honda K, Young VB, Pennathur S, van den Brink M, Reddy P (2016) Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol 17(5):505–513CrossRefGoogle Scholar
  13. 13.
    Swimm A, Giver CR, DeFilipp Z, Rangaraju S, Sharma A, Ulezko Antonova A, Sonowal R, Capaldo C, Powell D, Qayed M, Kalman D, Waller EK (2018) Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease. Blood 132(23):2506–2519CrossRefGoogle Scholar
  14. 14.
    Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, Ling L, Kosuri S, Maloy M, Slingerland JB, Ahr KF, Porosnicu Rodriguez KA, Shono Y, Slingerland AE, Docampo MD, Sung AD, Weber D, Alousi AM, Gyurkocza B, Ponce DM, Barker JN, Perales MA, Giralt SA, Taur Y, Pamer EG, Jenq RR, van den Brink MRM (2017) Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol 35(15):1650–1659CrossRefGoogle Scholar
  15. 15.
    Tanoue T, Atarashi K, Honda K (2016) Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16(5):295–309CrossRefGoogle Scholar
  16. 16.
    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 (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264):1079–1084CrossRefGoogle Scholar
  17. 17.
    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 (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264):1084–1089CrossRefGoogle Scholar
  18. 18.
    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 (2018) Gut microbiome influences efficacy of PD‑1-based immunotherapy against epithelial tumors. Science 359(6371):91–97CrossRefGoogle Scholar
  19. 19.
    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, Riquelme Sanchez EM, 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 (2018) Gut microbiome modulates response to anti-PD‑1 immunotherapy in melanoma patients. Science 359(6371):97–103CrossRefGoogle Scholar
  20. 20.
    Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF (2018) The commensal microbiome is associated with anti-PD‑1 efficacy in metastatic melanoma patients. Science 359(6371):104–108CrossRefGoogle Scholar
  21. 21.
    Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, Storti C, Triulzi T, Castelli C, Balsari A, Tagliabue E, Sfondrini L (2018) Modulation of pulmonary microbiota by antibiotic or probiotic aerosol therapy: A strategy to promote Immunosurveillance against lung metastases. Cell Rep 24(13):3528–3538CrossRefGoogle Scholar
  22. 22.
    Dubin K, Callahan MK, Ren B, Khanin R, Viale A, Ling L, No D, Gobourne A, Littmann E, Huttenhower C, Pamer EG, Wolchok JD (2016) Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 7:10391CrossRefGoogle Scholar
  23. 23.
    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 (2017) Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 28(6):1368–1379CrossRefGoogle Scholar
  24. 24.
    Wang F, Yin Q, Chen L, Davis MM (2018) Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. Proc Natl Acad Sci U S A 115(1):157–161CrossRefGoogle Scholar
  25. 25.
    Wang Y, Wiesnoski DH, Helmink BA, Gopalakrishnan V, Choi K, DuPont HL, Jiang ZD, Abu-Sbeih H, Sanchez CA, Chang CC, Parra ER, Francisco-Cruz A, Raju GS, Stroehlein JR, Campbell MT, Gao J, Subudhi SK, Maru DM, Blando JM, Lazar AJ, Allison JP, Sharma P, Tetzlaff MT, Wargo JA, Jenq RR (2018) Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 24(12):1804–1808.  https://doi.org/10.1038/s41591-018-0238-9 CrossRefPubMedGoogle Scholar
  26. 26.
    Luu M, Weigand K, Wedi F, Breidenbend C, Leister H, Pautz S, Adhikary T, Visekruna A (2018) Regulation of the effector function of CD8(+) T cells by gut microbiota-derived metabolite butyrate. Sci Rep 8(1):14430.  https://doi.org/10.1038/s41598-018-32860-x CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cremonesi E, Governa V, Garzon JFG, Mele V, Amicarella F, Muraro MG, Trella E, Galati-Fournier V, Oertli D, Däster SR, Droeser RA, Weixler B, Bolli M, Rosso R, Nitsche U, Khanna N, Egli A, Keck S, Slotta-Huspenina J, Terracciano LM, Zajac P, Spagnoli GC, Eppenberger-Castori S, Janssen KP, Borsig L, Iezzi G (2018) Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut 67(11):1984–1994CrossRefGoogle Scholar
  28. 28.
    Uribe-Herranz M, Bittinger K, Rafail S, Guedan S, Pierini S, Tanes C, Ganetsky A, Morgan MA, Gill S, Tanyi JL, Bushman FD, June CH, Facciabene A (2018) Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL‑12. JCI Insight 3(4):e94952.  https://doi.org/10.1172/jci.insight.94952 CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Kuczma MP, Ding ZC, Li T, Habtetsion T, Chen T, Hao Z, Bryan L, Singh N, Kochenderfer JN, Zhou G (2017) The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells. Oncotarget 8(67):111931–111942CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  • E. Holler
    • 1
    Email author
  • D. Weber
    • 1
  • D. Heudobler
    • 1
  • D. Wolff
    • 1
  • W. Herr
    • 1
  1. 1.Klinik und Poliklinik für Innere Medizin IIIKlinikum der Universität RegensburgRegensburgDeutschland

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