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

Cell Rep. 2019 Aug 20;28(8):2156-2168.e5. doi: 10.1016/j.celrep.2019.07.068.


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.

Keywords: immune response to cancer; immunomodulation; prostate cancer; tumor associated macrophages; tumor immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Polarity
  • Cellular Senescence*
  • Chemokine CXCL2 / administration & dosage
  • Chemokine CXCL2 / pharmacology
  • Humans
  • Inflammation / pathology
  • Macrophages / pathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Staging
  • Neutralization Tests
  • PTEN Phosphohydrolase / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Chemokine CXCL2
  • Receptors, Interleukin-8B
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • PTEN Phosphohydrolase