title: Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
abstract: Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.
authors.affiliation: 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2].
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.affiliation: 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2].
authors.forename: Alberto
authors.initials: A
authors.lastname: Toso
authors.affiliation: 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.affiliation: Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland.
authors.forename: Tanja Rezzonico
authors.initials: TR
authors.lastname: Jost
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland.
authors.forename: Rocco
authors.initials: R
authors.lastname: D'Antuono
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland.
authors.forename: Erica
authors.initials: E
authors.lastname: Montani
authors.affiliation: 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Escudero
authors.affiliation: Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.affiliation: Laboratory of Stem Cells in Cancer and Aging, (stemCHUS) Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital (CHUS), E15706 Santiago de Compostela, Spain.
authors.forename: Sabela
authors.initials: S
authors.lastname: Da Silva-Alvarez
authors.affiliation: Laboratory of Stem Cells in Cancer and Aging, (stemCHUS) Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital (CHUS), E15706 Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Eisenberger
authors.affiliation: Divisions of BioStatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Catapano
authors.affiliation: 1] Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland [2] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan I-20100, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.affiliation: 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
mesh_terms: D000818:Animals; D002465:Cell Movement; D016922:Cellular Senescence / Q000187:drug effects; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007113:Immunity, Innate; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000378:metabolism; D053582:Interleukin-1alpha / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019707:Receptors, Chemokine / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000494:pharmacology; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: C503133:Gr-1 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; D043823:Taxoids; D000077143:Docetaxel; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse