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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author 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, Alimonti Andrea,
Project Manipulation of senescence pathways for cancer therapy: from experimental models to clinic
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Original article (peer-reviewed)

Journal Nature
Volume (Issue) 515(7525)
Page(s) 134 - 7
Title of proceedings Nature
DOI 10.1038/nature13638


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.