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- Title
Tumour-infiltrating Gr-1<sup>+</sup> myeloid cells antagonize senescence in cancer.
- Authors
Di Mitri, Diletta; Toso, Alberto; Chen, Jing Jing; Alimonti, Andrea; Sarti, Manuela; Pinton, Sandra; Guccini, Ilaria; Catapano, Carlo; Jost, Tanja Rezzonico; D'Antuono, Rocco; Montani, Erica; Garcia-Escudero, Ramon; Da Silva-Alvarez, Sabela; Collado, Manuel; Eisenberger, Mario; Zhang, Zhe; Grassi, Fabio
- 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.
- Subjects
CANCER research; TUMORS; MYELOID leukemia; AGING; ONCOGENES
- Publication
Nature, 2014, Vol 515, Issue 7525, p134
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13638