Abstract 1522: Elevated polyamine levels generate an immunosuppressive oncogenic microenvironment

Abstract

Abstract Increased suprabasal epidermal activity of ornithine decarboxylase (ODC), a key regulatory enzyme in polyamine biosynthesis, stimulates cellular proliferation and vascularization in the underlying dermis, and promotes skin tumorigenesis after treatment with a single, subthreshold dose of a carcinogen in ODCER transgenic mice. Interestingly, skin tumor formation is also induced in ODCER transgenic mice by wounding and does not require prior carcinogen treatment. This wound-induced tumor formation is dependent on the polyamine-induction of sustained recruitment of inflammatory cells to the dermal wound site. Moreover, when weakly transformed (Ras activation) primary keratinocytes (Ker/Ras) were injected subcutaneously in syngeneic ODCER transgenic mice, tumor growth occurred while it did not in normal littermates. These data suggest the generation of an oncogenic stromal microenvironment in mice with elevated epidermal polyamine levels. Polyamine-Based Therapy (PaBT: combination of the well-characterized ODC inhibitor, difluoromethylornithine (DFMO), and an inhibitor of cellular polyamine transport, AMXT 1501) significantly inhibited tumor growth in wildtype FVB mice that were orthotopically injected with either syngeneic Ker/Ras cells or neu02 mammary tumor cells. Flow cytometry analyses of tumor inflammatory infiltrates revealed that PaBT significantly increased the percentage of CD3+ cell population (includes T cells and NK cells) and decreased the percentage of both F4/80+ (macrophage) and Gr-1+ (neutrophil and monocyte) subpopulations of CD45+ cells compared to tumors in control, non-treated mice. When PaBT treatment was stopped and tumors were resected, we re-challenged two weeks later with a second injection of neu02 tumor cells. Mice that had been previously treated with PaBT were protected from secondary tumor growth (demonstrating no or very little tumor growth) compared to mice that never received PaBT. In order to examine whether elevated polyamine biosynthesis suppresses a T-cell mediated adaptive immune response, we examined the effect of ODC overexpression in keratinocytes on a classic contact hypersensitivity (CHS) response test using ODCER transgenic mice. These mice showed reduced ear swelling in comparison to normal littermates together with reduced neutrophil infiltration and decreased migration of FITC-loaded dendritic cells to draining lymph nodes following hapten elicitation of CHS. Collectively, these data suggest that the immunosuppression mediated by increased epidermal ODC activity may contribute to an environment conducive to tumor growth, and, conversely, that depletion of tumor polyamines will block tumorigenesis in part by normalizing the stromal microenvironment and restoring tumor immune surveillance. (Supported by NIH grant CA070739 and funding from Aminex Therapeutics Inc) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1522. doi:1538-7445.AM2012-1522