Abstract 3646: The role of myeloid-derived suppressor cells in tumor development

Abstract

Abstract Myeloid-derived suppressor cells (MDSC) play an important role in regulation of immune response in cancer. They also have been implicated into promotion of tumor metastases and angiogenesis. We asked what role if any these myeloid cells can play in tumor formation associated in inflammation. To address this question we used previously described S100A9 deficient and S100A9 transgenic mice. S100A9, also known as calgranulin B or myeloid related protein 14 (MRP14), is a member of the S100 family of Ca2+ binding proteins. Previous studies have established that up-regulation of this protein in hematopoietic progenitor cells results in inhibition of dendritic cell maturation and accumulation of MDSC. We tested the role of MDSC in skin tumor formation using TgAC transgenic mice. These mice have activated k-ras mutation in keratinocytes. Upon topical treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) they develop skin papillomas. We generated double transgenic mice and demonstrated that in mice overexpressing S100A9 the frequency and number of papillomas increased dramatically comparing with wild-type TgAC mice. The formation of papillomas was also significantly accelerated. To confirm the critical role of myeloid cells in the observed effect we used bone marrow transfer from wild-type or S100A9 Tg mice into lethally irradiated TgAC mice. Transfer of S100A9 Tg bone marrow cells resulted in significantly more rapid and more extensive formation of papillomas in TPA treated mice than transfer of control bone marrow. To assess effect of TPA treatment on cell infiltrate into skin wild-type or S100A9Tg mice were treated with TPA for 3 weeks. Skin from S100A9Tg mice had significantly higher number of Gr-1+ myeloid cells and CD4+ T cells than skin from wild-type mice. No differences in F4/80 macrophages and CD11c+ dendritic cells were seen. To further evaluate the possible role of MDSC in tumor formation we treat control and S100A9 knockout (KO) mice with combination of carcinogen DMBA and TPA using accelerated skin carcinogenesis protocol. The absence of S100A9 substantially delayed the onset of papilloma and decreased the number of lesions as compared with wild-type mice. These results suggest that MDSC may play an important role in inflammation associated tumoregenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3646. doi:10.1158/1538-7445.AM2011-3646