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

// Eric T. Alexander 1 , Allyson Minton 1 , Molly C. Peters 1 , Otto Phanstiel IV 2 and Susan K. Gilmour 1 1 Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA 2 University of Central Florida, Biomolecular Research Annex, Orlando, FL 32826-3227, USA Correspondence to: Susan K. Gilmour, email: gilmours@mlhs.org Keywords: polyamines, difluoromethylornithine, transport inhibitor, immunomodulation, tumor microenvironment Received: June 03, 2017      Accepted: July 23, 2017      Published: August 24, 2017 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.