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

Diletta Di Mitri1, Michela Mirenda2, Jelena Vasilevska2

  • 1Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via A. Manzoni 113, 20089 Rozzano, Milan, Italy.

Cell Reports
|August 22, 2019
PubMed

Insights

Re-educating tumor-associated macrophages (TAMs) via CXCR2 blockade shows promise for inhibiting prostate cancer. Blocking CXCR2 promotes pro-inflammatory macrophages, inducing tumor cell senescence and inhibition.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Biology

Background:

  • Tumor-associated macrophages (TAMs) are key players in the tumor microenvironment, often supporting cancer progression.
  • Re-educating TAMs is a potential strategy for tumor inhibition, but its efficacy in prostate cancer remains unclear.

Purpose of the Study:

  • To investigate the role of C-X-C chemokine receptor type 2 (CXCR2) in prostate cancer-associated TAMs.
  • To explore the potential of targeting CXCR2 for therapeutic benefit in prostate cancer.

Main Methods:

  • Analysis of TAM infiltration and CXCR2 expression in Pten-null prostate tumors.
  • Pharmacological blockade of CXCR2 using a selective antagonist.
  • Infusion of CXCR2 knockout monocytes into Pten/Trp53-deficient mice.
  • Assessment of macrophage phenotype, tumor cell senescence, and tumor inhibition.

Main Results:

  • Pten-null prostate tumors exhibit high infiltration of TAMs expressing CXCR2.
  • CXCR2 activation by CXCL2 promotes an anti-inflammatory TAM phenotype.
  • CXCR2 blockade or knockout promotes a pro-inflammatory TAM phenotype, leading to tumor senescence and inhibition.
  • PTEN-deficient tumor cells show increased vulnerability to TNF-α-induced senescence due to elevated TNFR1.

Conclusions:

  • TAMs are viable therapeutic targets in prostate cancer.
  • CXCR2 blockade represents a promising strategy to reprogram TAMs towards an anti-tumorigenic, pro-inflammatory state.
  • This approach harnesses the anti-tumorigenic potential of macrophages to combat prostate cancer.
Keywords:
immune response to cancerimmunomodulationprostate cancertumor associated macrophagestumor immunology

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