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.
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.
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.
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.
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Legal entity responsible for the study
Institute of Oncology Research
All authors have declared no conflicts of interest.