Diletta Di Mitri 1 , 18 , Michela Mirenda 2 , 18 , Jelena Vasilevska 2 , 18 , Arianna Calcinotto 2 , Nicolas Delaleu 3 , 4 , 5 , Ajinkya Revandkar 2 , Veronica Gil 6 , Gunther Boysen 6 , Marco Losa 2 , Simone Mosole 2 , Emiliano Pasquini 2 , Rocco D’Antuono 7 , Michela Masetti 1 , Elena Zagato 2 , Giovanna Chiorino 8 , Paola Ostano 8 , Andrea Rinaldi 2 , Letizia Gnetti 9 , Mariona Graupera 10 , 11 , 12 , Ana Raquel Martins Figueiredo Fonseca 10 , 11 , 12 , Ricardo Pereira Mestre 17 , David Waugh 13 , Simon Barry 14 , Johann De Bono 6 , Andrea Alimonti 2 , 15 , 16 , 17 , 19 , ∗
20 August 2019
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-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.
Di Mitri et al. show that CXCR2 blockade in prostate cancer triggers TAMs re-education, leading to tumor inhibition. CXCR2-KO monocytes infused in Pten pc−/−; Trp53 pc−/− tumor-bearing mice differentiate into TNFα-releasing pro-inflammatory macrophages that induce senescence in tumor cells. PTEN-null tumors display higher sensitivity to TNF-α-induced senescence because of TNFR1 upregulation.