title: Pancreatic Cancer Cells Isolated from Muc1-Null Tumors Favor the Generation of a Mature Less Suppressive MDSC Population.
abstract: Mucin 1 (MUC1) is a transmembrane mucin glycoprotein that is over-expressed and aberrantly glycosylated in >80% of human pancreatic ductal adenocarcinoma (PDA) and is associated with poor prognosis. To understand the role of MUC1 in PDA, we have recently developed two mouse models of spontaneous PDA, one that expresses full-length human MUC1 transgene (KCM mice) and one that is null for MUC1 (KCKO mice). We have previously reported that KCM mice express high levels of myeloid derived suppressor cells (MDSCs) in their tumors and develop highly aggressive PDA. To further understand the underlying mechanism for high MDSC levels in KCM-tumors, we generated primary cell lines from KCM and KCKO-tumors. In this study, we report that MDSCs derived using KCM cells express significantly higher levels of arginase 1 and inducible nitric oxide synthase (markers associated with immune suppression) and lower levels of CD115 (a marker associated with maturation of myeloid cells) as compared to KCKO-derived MDSCs. Functionally, KCM-derived MDSCs secrete significantly higher levels of urea and nitric oxide (NO) when co-cultured with normal splenic cells as compared to KCKO-derived MDSCs. Data indicates that KCM-derived MDSCs remain immature and are more suppressive as compared to KCKO-derived MDSCs. This was further corroborated in vivo where MDSCs isolated from KCM-tumor-bearing mice retained their immature state and were highly suppressive as compared to MDSCs derived from KCKO-tumor-bearing mice. Finally, we show that KCM cells secrete significantly higher levels of prostaglandin E2 (PGE2), a COX-2 metabolite and a known driver of suppressive MDSCs as compared to KCKO cells. Thus, inhibiting PGE2 with a specific COX-2 inhibitor reverses the immunosuppressive and immature phenotype of KCM-derived MDSCs. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Amritha
authors.initials: A
authors.lastname: Kidiyoor
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Schettini
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Dahlia Marie
authors.initials: DM
authors.lastname: Besmer
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Stephen Lee
authors.initials: SL
authors.lastname: Rego
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Sritama
authors.initials: S
authors.lastname: Nath
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Jennifer Marie
authors.initials: JM
authors.lastname: Curry
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Lopamudra Das
authors.initials: LD
authors.lastname: Roy
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Dréau
authors.affiliation: Department of Biology, University of North Carolina at Charlotte , Charlotte, NC , USA.
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
keywords: COX-2; MDSC; immune suppression; mucin 1; pancreatic cancer