Abstract 3175: CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer

Abstract

Abstract Myeloid derived suppressor cells (MDSCs) are an immunosuppressive population of immature myeloid cells found in advanced stage cancer patients and mouse tumor models. MDSCs suppress T cell-mediated tumor clearance by production of inducible nitric oxide synthase (iNOS) and arginase, as well as through other mechanisms. The purpose of this study was to identify the factor(s) contributing to the pro-tumorigenic role of MDSCs in esophageal squamous cell carcinoma (ESCC). We have used an unbiased approach to search for changes in global gene expression profile of MDSCs derived from conditional p120-catenin knockout mice (L2-cre;p120ctnf/f, a model of oral-esophageal cancer; Stairs D.B., et al Cancer Cell 2011), compared to immature myeloid cells from age-matched wild-type mice. We have detected a dramatic increase in expression of the Cd38 gene in MDSCs, compared to control cells. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation and neutrophil chemotaxis. We find that CD38 expression in MDSCs is evident in several mouse tumor models, and CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production. We have identified novel tumor-derived factors, including IL-6, IGFBP-3 and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have demonstrated that monoclonal antibody-mediated targeting of CD38 results in suppressed tumor growth in vivo in a subcutaneous transplant model of ESCC. In conclusion, we have shown that expression of CD38 plays an important role in MDSC biology by promoting an enhanced immunosuppressive capacity and a more immature phenotype in vivo. We have also detected an expansion of CD38-positive MDSCs in peripheral blood of advanced stage cancer patients and propose targeting CD38 in vivo as an approach to cancer therapy. Supported by NCI P01CA098101. Citation Format: Tatiana A. Karakasheva, Todd J. Waldron, Evgeniy Eruslanov, Ju-Seog Lee, Shaun O'Brien, Devraj Basu, Sunil Singhal, Fabio Malavasi, Anil K. Rustgi. CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3175. doi:10.1158/1538-7445.AM2015-3175