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.
|Titolo:||Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer|
|Parole Chiave:||animals; disease progression; drug resistance, neoplasm; humans; immunity, innate; interleukin 1 receptor antagonist protein; interleukin-1alpha; male; mice; myeloid cells; PTEN phosphohydrolase; prostatic neoplasms; receptors, chemokine; receptors, interleukin-8B; taxoids; tumor escape; tumor microenvironment; cell aging; cell movement; medicine (all); multidisciplinary|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
|Data di pubblicazione:||6-nov-2014|
|Digital Object Identifier (DOI):||10.1038/nature13638|
|Appare nelle tipologie:||01 - Articolo su periodico|