Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8⁺ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.

中文翻译：

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靶向内源性己糖胺的生物合成使胰腺癌对抗PD1治疗敏感

胰腺导管腺癌（PDAC）被认为是高度免疫抑制和异质性肿瘤。尽管对肿瘤的遗传背景有了更深入的了解，并且对肿瘤的微环境有了更好的了解，但免疫检查点抑制剂疗法（靶向CTLA4，PD1，PDL1）对PDAC并不是很成功。强大的增生基质，以及富含透明质酸的广泛细胞外基质（ECM），在这种免疫逃避中起着不可或缺的作用。己糖胺生物合成途径（HBP）是糖酵解的分流途径，是癌细胞中的一个代谢节点，一方面可以促进生存途径，另一方面可以影响ECM中的透明质酸合成。该途径的限速酶谷氨酰胺-果糖酰胺基转移酶1（GFAT1），N-乙酰氨基葡萄糖（UDP-GlcNAc）。在当前的手稿，我们通过小分子谷氨酰胺类似物靶向此利用谷氨酰胺酶（6-重氮-5-氧代-升-norleucine [DON]）。我们的结果表明，DON降低了肿瘤细胞的自我更新潜能和转移能力。此外，用DON进行治疗可降低肿瘤微环境中的透明质酸和胶原蛋白，从而导致ECM的广泛重塑和CD8 ⁺ T细胞的浸润增加。此外，用DON治疗可使胰腺肿瘤对PD1疗法敏感，导致肿瘤消退并延长生存期。