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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)134-137
Number of pages4
JournalNature
Volume515
Issue number7525
DOIs
StatePublished - Nov 6 2014

ASJC Scopus subject areas

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    Di Mitri, D., Toso, A., Chen, J. J., Sarti, M., Pinton, S., Jost, T. R., D'Antuono, R., Montani, E., Garcia-Escudero, R., Guccini, I., Da Silva-Alvarez, S., Collado, M., Eisenberger, M., Zhang, Z., Catapano, C., Grassi, F., & Alimonti, A. (2014). Tumour-infiltrating Gr-1 + myeloid cells antagonize senescence in cancer. Nature, 515(7525), 134-137. https://doi.org/10.1038/nature13638