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.
Highlights
Every year, an estimated 270,000 deaths occur worldwide due to pancreatic cancer [1], and in the US, the 1- and 5-year survival rates for all stages combined are 25 and 6%, respectively [2]
We report that myeloid derived suppressor cells (MDSCs) derived using Pancreatic ductal adenocarcinoma (PDA) cell line expressing Mucin 1 (MUC1) (KCM) cells express significantly higher levels of arginase 1 and inducible nitric oxide synthase and lower levels of CD115 as compared to PDA cell line without MUC1 (KCKO)-derived MDSCs
tumor derived soluble factors (TDSFs) FROM MUC1 EXPRESSING PDA CELLS FAVOR THE EXPANSION OF MONOCYTIC MDSCs Bone marrow cells were cultured in media supplemented with GM-CSF and IL-4 with or without 30% v/v tumor cell conditioned media (TCCM) from KCM or KCKO to determine whether MUC1 expression in PDA cells affects MDSC expansion from bone marrows (BM) cells
Summary
An estimated 270,000 deaths occur worldwide due to pancreatic cancer [1], and in the US, the 1- and 5-year survival rates for all stages combined are 25 and 6%, respectively [2]. Therapies that are successful in treating other malignancies are relatively ineffective for pancreatic cancer possibly because cells evade immune recognition [3]. Cancer cells release pro-inflammatory factors that promote the generation of immune suppressor cells including myeloid derived suppressor cells (MDSCs) [3]. MDSCs play a prominent role in tumor induced immune suppression and are one of the major factors limiting the efficacy of immune therapies [4, 5]. MUC1 (CD227), a transmembrane mucin glycoprotein is aberrantly over-expressed in >80% of PDA. This suggests a pivotal role for MUC1 in the progression of PDA. Its role in tumor induced immune suppression and in the generation of MDSCs is not well known
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