Tumour-infiltrating Gr-[1.sup.+] myeloid cells antagonize senescence in cancer

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 (1-3). This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entr...

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Bibliographic Details
Published in:	Nature (London) Vol. 515; no. 7525; pp. 134 - 150
Main Authors:	Di Mitri, Diletta, Toso, Alberto, Chen, Jing Jing, Sarti, Manuela, Pinton, Sandra, Jost, Tanja Rezzonico, D'Antuono, Rocco, Montani, Erica, Garcia-Escudero, Ramon, Guccini, Ilaria, Da Silva-Alvarez, Sabela, Collado, Manuel, Eisenberger, Mario, Zhang, Zhe, Catapano, Carlo, Grassi, Fabio, Alimonth, Andrea
Format:	Journal Article
Language:	English
Published:	Nature Publishing Group 06-11-2014
Subjects:	Aging Blood cells Cells Development and progression Genetic aspects Physiological aspects Tumors United States Switzerland Spain
Online Access:	Get full text
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Summary:	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 (1-3). This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence (4-6). 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 (2,7) are massively infiltrated by a population of [CD11b.sup.+]Gr-[1.sup.+] myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-[1.sup.+] 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 Illra 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.sup.+] Gr-[1.sup.+] myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2) (8). 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.
ISSN:	0028-0836 1476-4687