title: Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.
abstract: Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Réanimation Médicale, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Llitjos
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Auffray
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Alby-Laurent
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousseau
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Merdji
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Bonilla
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Toubiana
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Belaïdouni
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Réanimation Médicale, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lucas
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Réanimation Médicale, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Chiche
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Réanimation Médicale, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pène
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005354:Fibrosarcoma / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism / Q000473:pathology*; D010538:Peritonitis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D051197:Toll-Like Receptor 4
keywords: Toll-like receptor; cancer; mouse; myeloid-derived suppressor cell; sepsis