TY - JOUR
T1 - Tumour-infiltrating Gr-1 + myeloid cells antagonize senescence in cancer
AU - Di Mitri, Diletta
AU - Toso, Alberto
AU - Chen, Jing Jing
AU - Sarti, Manuela
AU - Pinton, Sandra
AU - Jost, Tanja Rezzonico
AU - D'Antuono, Rocco
AU - Montani, Erica
AU - Garcia-Escudero, Ramon
AU - Guccini, Ilaria
AU - Da Silva-Alvarez, Sabela
AU - Collado, Manuel
AU - Eisenberger, Mario
AU - Zhang, Zhe
AU - Catapano, Carlo
AU - Grassi, Fabio
AU - Alimonti, Andrea
N1 - Publisher Copyright:
©2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/11/6
Y1 - 2014/11/6
N2 - 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.
AB - 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.
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U2 - 10.1038/nature13638
DO - 10.1038/nature13638
M3 - Article
C2 - 25156255
AN - SCOPUS:84912561603
SN - 0028-0836
VL - 515
SP - 134
EP - 137
JO - Nature
JF - Nature
IS - 7525
ER -