Di Mitri, DilettaMirenda, MichelaVasilevska, JelenaCalcinotto, AriannaDelaleu, NicolasRevandkar, AjinkyaGil, VeronicaBoysen, GuntherLosa, MarcoMosole, SimonePasquini, EmilianoAntuono, Rocco D'Masetti, MichelaZagato, ElenaChiorino, GiovannaOstano, PaolaRinaldi, AndreaGnetti, LetiziaGraupera i Garcia-Milà, MarionaFigueiredo, Ana Raquel MartinsPereira Mestre, RicardoWaugh, DavidBarry, SimonBono, Johann Sebastian deAlimonti, Andrea2020-10-202020-10-202019-08-20https://hdl.handle.net/2445/171366Tumor-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.19 p.application/pdfengcc by-nc-nd (c) Di Mitri et al., 2019http://creativecommons.org/licenses/by-nc-nd/3.0/es/Càncer de pròstataMacròfagsCèl·lules TProstate cancerMacrophagesT cellsinfo:eu-repo/semantics/article2020-10-13info:eu-repo/semantics/openAccess31433989