Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer

Diletta Di Mitri, Michela Mirenda, Jelena Vasilevska, Arianna Calcinotto, Nicolas Delaleu, Ajinkya Revandkar, Veronica Gil, Gunther Boysen, Marco Losa, Simone Mosole, Emiliano Pasquini, Rocco D'Antuono, Michela Masetti, Elena Zagato, Giovanna Chiorino, Paola Ostano, Andrea Rinaldi, Letizia Gnetti, Mariona Graupera, Ana Raquel Martins Figueiredo FonsecaRicardo Pereira Mestre, David Waugh, Simon Barry, Johann De Bono, Andrea Alimonti

Research output: Contribution to journalArticlepeer-review

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 Ptenpc-/-; Trp53pc-/- mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-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.

Original languageEnglish
Pages (from-to)2156-2168.e5
JournalCell Reports
Volume28
Issue number8
DOIs
Publication statusPublished - Aug 20 2019

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