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Original Article
Gut microbiota modulate T cell trafficking into human colorectal cancer
  1. Eleonora Cremonesi1,
  2. Valeria Governa2,
  3. Jesus Francisco Glaus Garzon3,
  4. Valentina Mele1,
  5. Francesca Amicarella1,
  6. Manuele Giuseppe Muraro2,
  7. Emanuele Trella2,
  8. Virginie Galati-Fournier4,
  9. Daniel Oertli5,
  10. Silvio Raffael Däster5,
  11. Raoul A Droeser5,
  12. Benjamin Weixler5,
  13. Martin Bolli6,
  14. Raffaele Rosso7,
  15. Ulrich Nitsche8,
  16. Nina Khanna9,
  17. Adrian Egli10,
  18. Simone Keck4,
  19. Julia Slotta-Huspenina11,
  20. Luigi M Terracciano12,
  21. Paul Zajac2,
  22. Giulio Cesare Spagnoli2,
  23. Serenella Eppenberger-Castori12,
  24. Klaus-Peter Janssen8,
  25. Lubor Borsig3,
  26. Giandomenica Iezzi1
  1. 1 Cancer Immunotherapy, Department of Biomedicine, University of Basel, Basel, Switzerland
  2. 2 Oncology Surgery, Department of Biomedicine, University of Basel, Basel, Switzerland
  3. 3 Institute of Physiology, University of Zürich, Zürich, Switzerland
  4. 4 Pediatric Surgery, University Children’s Hospital, University of Basel, Basel, Switzerland
  5. 5 Department of General Surgery, University Hospital Basel, Basel, Switzerland
  6. 6 Department of Visceral Surgery, St. Claraspital, Basel, Switzerland
  7. 7 Department of Visceral Surgery, Ospedale Civico Lugano, Lugano, Switzerland
  8. 8 Department of Surgery, Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany
  9. 9 Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland
  10. 10 Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland
  11. 11 Institute of Pathology, Technical University of Munich, Munich, Germany
  12. 12 Institute of Pathology, University of Basel, Basel, Switzerland
  1. Correspondence to Dr Giandomenica Iezzi, Cancer Immunotherapy, Department of Biomedicine, University of Basel, Hebelstrasse 20, Basel 4031, Switzerland; giandomenica.iezzi{at}usb.ch

Abstract

Objective Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers.

Design Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing.

Results CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival.

Conclusions Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

  • colorectal cancer
  • immune response
  • chemokines
  • T lymphocytes
  • bacterial translocation

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Footnotes

  • Contributors GI conceived and designed experiments, analysed and interpreted results, obtained funding and wrote the manuscript; EC designed and performed experiments, analysed and interpreted results and wrote the manuscript; FA, JFGG, VG, MGM, VM, VG-F, SK, JS-H and LMT contributed to design and conduction of experiments and to analysis and interpretation of data; DO, SRD, MB, RR, BW, and UN contributed to conception of research and data collection; GCS, NK, AE, PZ, SE-C, K-PJ and LB contributed to conception of research, design and conduction of experiments, analysis and interpretation of data and writing of the manuscript.

  • Funding Swiss National Science Foundation (SNF PP00P3-133699 and PP00P3-159262), University of Basel (Unibas Förderung des Akademischen Mittelbaus) and Department of Surgery, Basel University Hospital.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval EKBB/EKNZ (study protocol n. 2014-388), Ethics Committee of the Faculty of Medicine of the TUM (#1926/2007), Cantonal Veterinary Office Basel-Stadt (licence n. 2266), Cantonal Veterinary Office Zürich (licence n. 35/2014).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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