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

Abstract

Summary 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 Pten pc−/− ; Trp53 pc−/− 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.

Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

“…7 8 11 Therefore, repolarization of TAMs to an anti-tumor M1-like phenotype represents an attractive strategy for tumor immunotherapies. [21][22][23][24][25][26][27] In this study, we have demonstrated for the first time that, through costimulation of mCD14 and hCD32a, LTF-IC is able to drive the conversion of TAMs into M1-like phenotype characterized by strong production of TNF-α and GzmB and potent tumoricidal activity. The hCD32a transgene enabled mouse TAMs responding to LTF-IC in a fashion similar to human macrophages.…”

“…8 20-25 Pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the reeducation of TAMs toward a proinflammatory phenotype, leading to senescence and tumor inhibition in prostate cancer. 22 Intravenous IgG impaired tumor progression and metastasis in a Fc receptor-dependent and macrophagedependent manner, attributable to intravenous IgG skewing of M2 macrophages toward M1 cells. 26 Additionally, particulate yeast-derived β-glucan converted TAMs into immune-stimulating phenotype through the Dectin-1-Syk-Card9-Erk pathway, leading to reduced tumor progression.…”

Fibronectin in Cancer: Friend or Foe

“…Therefore, for tumor patients in a very early clinical stage, in addition to the traditional surgery, chemotherapies, and radiotherapies or recently prevailing immune checkpoint blockade therapies [353][354][355], therapeutic strategies can be formed by inducing overexpression of FN in newly transformed tumor cells and force tumor cells into senescent state or cell cycle arrest followed by cell apoptosis, if FN is proved to be a regulator for senescent induction by enhancing ER stresses. Alternatively, tumor senescence and subsequently apoptosis can be induced circumventing alteration of FN expression level [356,357]. However, one need to use caution that these FN-based therapeutic strategies should not be practiced once CTCs are identified from tumor patients' blood samples in that elevated levels of endogenous and thus periFN assembly in tumor cells may make FN high CTCs colonize more and form more metastatic tumor nodules in distant organs, unless there are strategies to reverse FN high CTCs back to pro-epithelial phenotypes that tend to render CTCs suffer more from anoikis and mechanical stresses and injuries.…”

Spatially-Resolved Live Cell Tagging and Isolation Using Protected Photoactivatable Cell Dyes

“…We also observed upregulation of coagulation factors F3, F7, F10, and Plau, and peptidases Adam8, Tpp1, Furin, and Npepps, suggesting tumor-periphery associated macrophages are mounting a wound-repair response and actively remodeling the local vasculature and lung stroma. Notably, among gene programs significantly negatively correlated with location at the tumor periphery, we found differential 270 expression of Cxcr2, which has been previously associated with deep-tumor infiltrating tumorassociated macrophages and an anti-inflammatory phenotype 26 . In the "non-periphery-like" cells we also found upregulation of genes involved in protein homeostasis (Hspa1a, Hspe1, Dnajc3, Hsp90ab1), RNA silencing (Dicer1, Ago1), proteasome components (Psmc5, Psmb1, Psme1), as well as alterations in cellular respiration and glycolysis (Idh2, Idh3g, Idh3b, Mdh1).…”