| Autor: |
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 Fonseca, Ricardo Pereira Mestre, David Waugh, Simon Barry, Johann De Bono, Andrea Alimonti |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 28, Iss 8, Pp 2156-2168.e5 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2019.07.068 |
| Popis: |
Summary: 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. : Di Mitri et al. show that CXCR2 blockade in prostate cancer triggers TAMs re-education, leading to tumor inhibition. CXCR2-KO monocytes infused in Ptenpc−/−; Trp53pc−/− 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. Keywords: prostate cancer, tumor immunology, immunomodulation, immune response to cancer, tumor associated macrophages |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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