A novel polyamine blockade therapy activates an anti-tumor immune response

Abstract

Most tumors maintain elevated levels of polyamines to support their growth and survival. This study explores the anti-tumor effect of polyamine starvation via both inhibiting polyamine biosynthesis and blocking the upregulated import of polyamines into the tumor. We demonstrate that polyamine blockade therapy (PBT) co-treatment with both DFMO and a novel polyamine transport inhibitor, Trimer PTI, significantly inhibits tumor growth more than treatment with DFMO or the Trimer PTI alone. The anti-tumor effect of PBT was lost in mice where CD4+ and CD8+ T cells were antibody depleted, implying that PBT stimulates an anti-tumor immune effect that is T-cell dependent. The PBT anti-tumor effect was accompanied by an increase in granzyme B+, IFN-γ+ CD8+ T-cells and a decrease in immunosuppressive tumor infiltrating cells including Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs), CD4+CD25+ Tregs, and CD206+F4/80+ M2 macrophages. Stimulation with tumor-specific peptides elicited elevated antigen-specific IFN-γ secretion in splenocytes from PBT-treated mice, indicating that PBT treatment stimulates the activation of T-cells in a tumor-specific manner. These data show that combined treatment with both DFMO and the Trimer PTI not only deprives polyamine-addicted tumor cells of polyamines, but also relieves polyamine-mediated immunosuppression in the tumor microenvironment, thus allowing the activation of tumoricidal T-cells.

Polyamine synthesis as a target of MYC oncogenes

“…Considering the central role of polyamine metabolism in many cancer hallmarks, ample possibilities remain for further neuroblastoma combination therapies. One obvious strategy is to combine the inhibition of polyamine biosynthesis with targeting polyamine import, which was successful in neuroblastoma cell culture studies (23) and in a mouse melanoma xenograft model (151). Interestingly, this combined polyamine blocking treatment in vivo resulted in increased immune response (151).…”

Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer

“…DFMO alone or in combination with the statin rosuvastatin reduced polyamines and enhanced natural killer cell activity associated with cancer prevention in the azoxymethane-induced model of colon carcinogenesis(95). Combination therapy with DFMO and a polyamine transport inhibitor reduced tumor cell polyamines and relieved immunosuppression in the microenviron-THEMATIC MINIREVIEW: Polyamines and cancer risk factors ment allowing activation of anti-tumor T-cells to reduce tumor growth in another mouse model of colon cancer(60). Polyamines have been broadly implicated in the function of normal immune cells(96).…”

Induction and Prevention of Gastric Cancer with Combined Helicobacter Pylori and Capsaicin Administration and DFMO Treatment, Respectively

“…In our mouse model, DFMO acts by inhibiting IL-6 and promoting IFN-γ cytokine release ( Figure 6), plus it enhances antitumor CD8 + T-cell infiltration and augments adoptive T-cell therapy. Furthermore, DFMO impairs the suppressive activity of myeloid-derived suppressor cells (MDSC), reverses tumor-induced immunosuppressive mechanisms, and invokes a measurable antitumor immune response [22,49]. Consequently, DFMO treatment may serve as a preventive measure against gastric tumorigenesis induced by capsaicin consumption and H. pylori infection.…”