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

D Di Mitri, A Toso, JJ Chen, M Sarti, S Pinton, TR Jost… - Nature, 2014 - nature.com
D Di Mitri, A Toso, JJ Chen, M Sarti, S Pinton, TR Jost, R D'Antuono, E Montani…
Nature, 2014nature.com
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 …
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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