RT Journal Article
SR Electronic
T1 Gut microbiota modulate T cell trafficking into human colorectal cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2016-313498
DO 10.1136/gutjnl-2016-313498
A1 Eleonora Cremonesi
A1 Valeria Governa
A1 Jesus Francisco Glaus Garzon
A1 Valentina Mele
A1 Francesca Amicarella
A1 Manuele Giuseppe Muraro
A1 Emanuele Trella
A1 Virginie Galati-Fournier
A1 Daniel Oertli
A1 Silvio Raffael Däster
A1 Raoul A Droeser
A1 Benjamin Weixler
A1 Martin Bolli
A1 Raffaele Rosso
A1 Ulrich Nitsche
A1 Nina Khanna
A1 Adrian Egli
A1 Simone Keck
A1 Julia Slotta-Huspenina
A1 Luigi M Terracciano
A1 Paul Zajac
A1 Giulio Cesare Spagnoli
A1 Serenella Eppenberger-Castori
A1 Klaus-Peter Janssen
A1 Lubor Borsig
A1 Giandomenica Iezzi
YR 2018
UL http://gut.bmj.com/content/early/2018/02/06/gutjnl-2016-313498.abstract
AB 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.