PO.CL05.05 · 临床研究
游离型和包裹型衣霉素通过阻断K-Ras G12D表达,显著增强吉西他滨对胰腺导管腺癌细胞中PD-L1的抑制
Free and encapsulated tunicamycin significantly enhances the suppression of PD-L1 by gemcitabine through blocking K-Ras G12D expression in pancreatic ductal adenocarcinoma cells
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摘要 Abstract
中文摘要
胰腺导管腺癌(PDAC)仍是全球癌症死亡的主要原因之一,在美国退伍军人中亦然,预计到2040年将成为第二大死因。标准治疗方案包括手术切除(在可行时)、化疗、靶向治疗、免疫治疗和放疗。这些治疗可单独或联合施用。遗憾的是,这些治疗方案并未显著改善PDAC患者的总生存率。因此,目前PDAC的一线治疗仍是FOLFIRINOX(氟尿嘧啶、亚叶酸钙、奥沙利铂和伊立替康的联合方案)和吉西他滨(GEM),二者单用或与nab-紫杉醇联合使用。虽然对化疗(如单用吉西他滨或与其他药物联用)可出现初始反应,但随后往往产生耐药。这种耐药通过JAK-STAT通路导致PDAC细胞中程序性死亡配体1(PD-L1)表达增加,对免疫治疗构成重大挑战。因此,迫切需要靶向疗法来克服这些局限。我们的研究发现衣霉素(Tunicamycin,TM)——一种糖基化抑制剂类抗生素——是一种有效靶向PDAC细胞并显著降低GEM诱导的PD-L1生成的强效药物。我们发现,用0.25 μM剂量的游离型或纳米包裹型衣霉素(NP TM)处理Panc-1和KPC细胞48小时,可克服与吉西他滨相关的局限。具体而言,我们观察到0.5 μM的吉西他滨处理未能抑制PD-L1表达;然而,当与TM联合时,吉西他滨在体外和体内均显著降低了这些细胞中的PD-L1水平。尽管TM调控PD-L1的机制尚未完全阐明,但既往研究表明K-RAS突变可通过激活MAPK/ERK通路直接影响PD-L1表达,而衣霉素可抑制该通路。因此,我们假设TM通过抑制K-RAS G12D来降低PDAC细胞中的PD-L1表达。(这些研究由VA Merit基金资助)
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading causes of cancer mortality worldwide, including among U.S. Veterans, and it is expected to become the second leading cause by 2040. The standard treatment options include surgical resection (when possible), chemotherapy, targeted therapy, immunotherapy, and radiation therapy. These treatments can be administered individually or in combination. Unfortunately, these treatment options have not significantly improved overall survival rates for patients with PDAC. Thus, currently, the first-line treatments for PDAC are still FOLFIRINOX (a combination of fluorouracil, leucovorin, oxaliplatin, and irinotecan) and Gemcitabine (GEM), either alone or in combination with nab-paclitaxel. While initial responses to chemotherapy, such as Gemcitabine alone or with other agents, can occur, these are often followed by the development of resistance. This resistance leads to increased programmed death-ligand 1 (PD-L1) expression in PDAC cells via the JAK-STAT pathway, posing a significant challenge for immunotherapy. Consequently, there is an urgent need for targeted therapies to overcome these limitations. Our research has identified Tunicamycin (TM), a glycosylation inhibitor antibiotic, as a potent agent that effectively targets PDAC cells and significantly reduces GEM-induced PD-L1 production. We found that treating Panc-1 and KPC cells with free or nanoencapsulated Tunicamycin ( NP TM) at a dose of 0.25 μM for 48 hours can overcome the limitations associated with Gemcitabine. Specifically, we observed that Gemcitabine treatment at 0.5 μM did not suppress PD-L1 expression; however, when combined with TM, Gemcitabine significantly reduced PD-L1 levels in these cells in vitro and in vivo . Although the mechanism by which TM regulates PD-L1 is not fully understood, previous studies have shown that K-RAS mutations can directly influence PD-L1 expression by activating the MAPK/ERK pathway, which Tunicamycin inhibits. Therefore, we hypothesize that TM reduces PD-L1 expression in PDAC cells by suppressing K-RAS G12D . (These studies are supported by the VA Merit grants)
利益披露 Disclosure
A. H. Breier, None..
S. P. Upadhyay, None..
O. Ommi, None..
S. Bossmann, None..
S. K. Banerjee, None..
S. Banerjee, None.