A Novel Polyamine Blockade Therapy Activates An Anti-Tumor Immune Response

Keywords

Difluoromethylornithine; Immunomodulation; Polyamines; Transport inhibitor; Tumor microenvironment

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 tumorspecific 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.

Publication Date

1-1-2017

Publication Title

Oncotarget

Volume

8

Issue

48

Number of Pages

84140-84152

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.18632/oncotarget.20493

Socpus ID

85031033560 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85031033560

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