For this study, immunophenotyping of PTEN null prostate murine models was performed by flow cytometry and gene expression analysis. Subsequently immunohistochemistry and immunofluorescence staining was utilized to detect macrophage infiltration in the tumor and markers of proliferation and senescence in the murine tissue. The authors 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. 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 functional status, 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.
The authors concluded that their results suggest TAMs as a target for prostate cancer therapy. Furthermore, these new therapeutic strategies have the potential to harness the anti-tumorigenic potential of macrophages in prostate cancer.
Speaker: Diletta Di Mitri, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Co-Authors: J. Vasilevska (BELLINZONA, Switzerland) A. Calcinotto (BELLINZONA, Switzerland) V. Gil (SUTTON, United Kingdom) G. Boysen (SUTTON, United Kingdom) A. Revandkar (BELLINZONA, Switzerland) D. Waugh (Belfast, United Kingdom) S. Barry (CAMBRIDGE, United Kingdom) J. De Bono (Sutton, United Kingdom) A. Alimonti (Bellinzona, Switzerland)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain