Citation
- Authors: Di Mitri, D., Mirenda, M., Vasilevska, J., Calcinotto, A., Delaleu, N., Revandkar, A., Gil, V., Boysen, G., Losa, M., Mosole, S., Pasquini, E., D'Antuono, R., Masetti, M., Zagato, E., Chiorino, G., Ostano, P., Rinaldi, A., Gnetti, L., Graupera, M., Martins Figueiredo Fonseca, A. R., Pereira Mestre, R., Waugh, D., Barry, S., De Bono, J., Alimonti, A.
- Year: 2019
- Journal: Cell Rep 28 2156-2168 e5
- Applications: in vitro / DNA / jetPRIME
- Cell type: TRAMP-C1
Description: Mouse prostate gland carcinoma cells.
Method
CRISPR KO
Abstract
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.