Pancreatic Cancer Cells Isolated from Muc1-Null Tumors Favor the Generation of a Mature Less Suppressive MDSC Population.
Pancreatic Cancer Cells Isolated from Muc1-Null Tumors Favor the Generation of a Mature Less Suppressive MDSC Population.
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DOI：
10.3389/fimmu.2014.00067
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发表时间：
2014
影响因子：
7.3
通讯作者：
Mukherjee P
中科院分区：
文献类型：
--
作者：
Kidiyoor A;Schettini J;Besmer DM;Rego SL;Nath S;Curry JM;Roy LD;Dréau D;Mukherjee P
粘蛋白1（MUC 1）是一种跨膜粘蛋白糖蛋白，在>80%的人胰腺导管腺癌（PDA）中过度表达和异常糖基化，并与不良预后相关。为了了解MUC 1在PDA中的作用，我们最近开发了两种自发性PDA小鼠模型，一种表达全长人MUC 1转基因（KCM小鼠），另一种为MUC 1无效（KCKO小鼠）。我们以前曾报道，KCM小鼠表达高水平的髓源性抑制细胞（MDSC）在他们的肿瘤和发展高度侵袭性PDA。为了进一步理解KCM肿瘤中高MDSC水平的潜在机制，我们从KCM和KCKO肿瘤产生了原代细胞系。在这项研究中，我们报告说，使用KCM细胞衍生的MDSC表达显着更高水平的辅酶I酶1和诱导型一氧化氮合酶（与免疫抑制相关的标志物）和较低水平的CD 115（与骨髓细胞成熟相关的标志物）相比，KCKO衍生的MDSC。在功能上，与KCKO衍生的MDSC相比，当与正常脾细胞共培养时，KCM衍生的MDSC分泌显著更高水平的尿素和一氧化氮（NO）。数据表明，与KCKO衍生的MDSC相比，KCM衍生的MDSC保持不成熟并且更具抑制性。这在体内得到了进一步证实，其中从携带KCM肿瘤的小鼠分离的MDSC保留了它们的未成熟状态，并且与来源于携带KCKO肿瘤的小鼠的MDSC相比具有高度抑制性。最后，我们表明，KCM细胞分泌显着更高水平的前列腺素E2（PGE 2），考克斯-2代谢产物和已知的驱动程序的抑制MDSC相比，KCKO细胞。因此，用特定的考克斯-2抑制剂抑制PGE 2可以逆转KCM衍生的MDSC的免疫抑制和不成熟表型。这是第一份明确表明胰腺肿瘤相关MUC 1在功能性MDSC发育中的功能性作用的报告。
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.