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Genitourinary tumours, prostate

4922 - Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence enhancement and tumor inhibition in advanced prostate cancer

Date

10 Sep 2017

Session

Genitourinary tumours, prostate

Presenters

Diletta Di Mitri

Citation

Annals of Oncology (2017) 28 (suppl_5): v269-v294. 10.1093/annonc/mdx370

Authors

D. Di Mitri1, J. Vasilevska1, A. Calcinotto1, V. Gil2, G. Boysen2, A. Revandkar1, D. Waugh3, S. Barry4, J. de Bono5, A. Alimonti6

Author affiliations

  • 1 Molecular Oncology, IOR, 6500 - BELLINZONA/CH
  • 2 Cancer Biomarkers Team, Royal Marsden NHS Foundation Trus, sSM2 - SUTTON/GB
  • 3 Centre For Cancer Research And Cell Biology, Queen's University Belfast - Centre for Cancer Research and Cell Biology, BT9 7AE - Belfast/GB
  • 4 Li Ka Shing Centre, IMED Oncology AstraZeneca, 00 - CAMBRIDGE/GB
  • 5 Division Of Clinical Studies, Prostate Cancer Targeted Therapy Group, Institute of Cancer Research Royal Marsden Hospital, SM2 5PT - Sutton/GB
  • 6 Molecular Oncology, IOR/IOSI, Bellinzona/CH
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Abstract 4922

Background

Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports tumorigenesis. TAMs re-education instead that eradication has been recently proposed as a strategy to promote tumor inhibition.

Methods

We performed an immunophenotyping of Pten null prostate murine models by flow cytometry and gene expression analysis. Immunoistochemistry and immunofluorescence sainings were utilized to detect macrophages infiltration in the tumor and marker of proliferation and senescence in the tissue.

Results

We have found that aggressive prostate tumors are strongly infiltrated by TAMs that express alternatively activated M2 markers. Unexpectedly chemokines binding to the C-X-C chemokine receptor type 2 (CXCR2) were among the most upregulated factors secreted by Pten null tumors and controlled the functional polarization of TAMs toward an “M2-like” functional status. Pharmacological blockade of the CXCR2 receptor in different tumor models in vivo promoted the re-education of TAMs toward a pro-inflammatory phenotype, which resulted in induction of senescence and tumor inhibition. Strikingly, infusions of CXCR2 knockout monocytes in Ptenpc-/-; Trp53pc-/- mice demonstrated that inhibition of CXCR2 does not interfere with the tumor recruitment of monocytes but prevented the polarization of TAMs in M2-like resulting in an increased percentage of TNFα-releasing M1-like macrophages in the tumor microenvironment. Moreover, tumor cells harboring PTEN deletion were more sensitive to TNFα-induced senescence when compared to PTEN WT tumors due to increased levels of TNFR1.

Conclusions

Taken together our results identify TAMs as a target for prostate cancer therapy and describe new therapeutic strategies to harness the anti-tumorigenic potential of macrophages in cancer.

Clinical trial identification

Legal entity responsible for the study

Institute of Oncology Research

Funding

ERC/Steiner

Disclosure

All authors have declared no conflicts of interest.

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