Journal
CELL REPORTS
Volume 28, Issue 8, Pages 2156-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.068
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Funding
- European Research Council (ERC) [261342]
- ERC [683136]
- Josef Steiner Foundation
- Helmut Horten Foundation
- Krebsliga [KFS 3505-08-2014]
- SNF (Ambizione) [PZ00P3_136612]
- AIRC [19141]
- European Research Council (ERC) [683136, 261342] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [PZ00P3_136612] Funding Source: Swiss National Science Foundation (SNF)
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Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Pten(pc-/-); Trp53(pc-/-) mice differentiated in tumor necrosis factor alpha (TNF-alpha)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-alpha-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.
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