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. 2014 Nov 6;515(7525):134-7.
doi: 10.1038/nature13638. Epub 2014 Aug 24.

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer

Diletta Di Mitri  1 , Alberto Toso  1 , Jing Jing Chen  2 , Manuela Sarti  3 , Sandra Pinton  3 , Tanja Rezzonico Jost  4 , Rocco D'Antuono  4 , Erica Montani  4 , Ramon Garcia-Escudero  5 , Ilaria Guccini  3 , Sabela Da Silva-Alvarez  6 , Manuel Collado  6 , Mario Eisenberger  7 , Zhe Zhang  8 , Carlo Catapano  3 , Fabio Grassi  9 , Andrea Alimonti  2
Affiliations

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer

Diletta Di Mitri et al. Nature. .

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.

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