Journal
NATURE
Volume 515, Issue 7525, Pages 134-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13638
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Funding
- Department of Defense Prostate Cancer Research Program [W81XWH-10-2-0056, W81XWH-10-2-0046]
- Swiss national science foundation (SNF) grant Ambizione [PZ00P3_136612/1]
- European Society for Medical Oncology (ESMO) translational research award
- Swiss Bridge Award
- PEOPLE-IRG [22484]
- European Research Council [ERCsg 261342]
- ABREOC
- Train COFUND Marie Curie
- Fondazione IBSA
- Swiss National Science Foundation (SNF) [PZ00P3_136612] Funding Source: Swiss National Science Foundation (SNF)
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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(1-3). This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence(4-6). Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours inmice(2,7) 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)(8). 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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