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Title: Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer
Author: Di Mitri, Diletta
Mirenda, Michela
Vasilevska, Jelena
Calcinotto, Arianna
Delaleu, Nicolas
Revandkar, Ajinkya
Gil, Veronica
Boysen, Gunther
Losa, Marco
Mosole, Simone
Pasquini, Emiliano
Antuono, Rocco D'
Masetti, Michela
Zagato, Elena
Chiorino, Giovanna
Ostano, Paola
Rinaldi, Andrea
Gnetti, Letizia
Graupera i Garcia-Milà, Mariona
Figueiredo, Ana Raquel Martins
Pereira Mestre, Ricardo
Waugh, David
Barry, Simon
Bono, Johann Sebastian de
Alimonti, Andrea
Keywords: Càncer de pròstata
Cèl·lules T
Prostate cancer
T cells
Issue Date: 20-Aug-2019
Publisher: Cell Press
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.
Note: Reproducció del document publicat a:
It is part of: Cell Reports, 2019, vol. 28, num. 8, p. 2156-2168
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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