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

      1 , 18 , 2 , 18 , 2 , 18 , 2 , 3 , 4 , 5 , 2 , 6 , 6 , 2 , 2 , 2 , 7 , 1 , 2 , 8 , 8 , 2 , 9 , 10 , 11 , 12 , 10 , 11 , 12 , 17 , 13 , 14 , 6 , 2 , 15 , 16 , 17 , 19 ,

      Cell Reports

      Cell Press

      prostate cancer, tumor immunology, immunomodulation, immune response to cancer, tumor associated macrophages

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          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.

          Graphical Abstract


          • CXCR2 blockade drives re-education of tumor-associated macrophages (TAMs)

          • Infusion of CXCR2-KO monocytes in tumor-bearing mice blocks tumor progression

          • PTEN deletion sensitizes tumor cells to TNF-α-induced senescence and growth arrest


          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.

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          Most cited references 20

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          Essential role of Stat6 in IL-4 signalling.

          Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.
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            The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.

            Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.
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              HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.

              Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HRG relies substantially on downregulation of placental growth factor (PlGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PlGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment. Copyright © 2011 Elsevier Inc. All rights reserved.

                Author and article information

                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                20 August 2019
                20 August 2019
                20 August 2019
                : 28
                : 8
                : 2156-2168.e5
                [1 ]Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via A. Manzoni 113, 20089 Rozzano, Milan, Italy
                [2 ]Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland
                [3 ]Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
                [4 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland
                [5 ]2C SysBioMed, 6646 Contra, Switzerland
                [6 ]The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK
                [7 ]Institute for Research in Biomedicine (IRB), 6500 Bellinzona, Switzerland
                [8 ]Cancer Genomics Lab, Fondazione Edo ed Elvo Tempia, Via Malta, 3, 13900 Biella, Italy
                [9 ]Pathology Unit, University Hospital of Parma, 43126 Parma, Italy
                [10 ]Vascular Signalling Laboratory, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
                [11 ]Program Against Cancer Therapeutic Resistance (ProCURE), Barcelona, Spain
                [12 ]CIBERONC, Madrid, Spain
                [13 ]Movember Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
                [14 ]IMED Oncology AstraZeneca, Li KaShing Centre, Cambridge, UK
                [15 ]Faculty of Medicine, Università della Svizzera Italiana, 1011 Lugano, Switzerland
                [16 ]Department of Medicine, University of Padua, 35131 Padua, Italy
                [17 ]Medical Oncology, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland
                Author notes
                []Corresponding author andrea.alimonti@

                These authors contributed equally


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