Metabolome of Pancreatic Juice Delineates Distinct Clinical Profiles of Pancreatic Cancer and Reveals a Link between Glucose Metabolism and PD-1+ Cells
Metabolome of Pancreatic Juice Delineates Distinct Clinical Profiles of Pancreatic Cancer and Reveals a Link between Glucose Metabolism and PD-1+ Cells
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DOI：
10.1158/2326-6066.cir-19-0403
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发表时间：
2020-04-01
影响因子：
10.1
通讯作者：
Marchesi, Federica
中科院分区：
文献类型：
--
作者：
Cortese, Nina;Capretti, Giovanni;Marchesi, Federica
更好地了解包括胰腺导管腺癌（PDAC）在内的胰腺疾病是一项紧迫的医学需求，但术前鉴别诊断进展甚微，阻碍了治疗策略的合理选择。胰腺癌患者的临床管理将受益于与多种胰腺疾病明显相关的变量的识别。我们通过 H-1 核磁共振研究了 40 名患有不同胰腺疾病的患者胰液（收集胰腺产物的生物液体）的代谢组指纹。代谢变量将 PDAC 与其他侵袭性较弱的胰腺疾病区分开来，并确定了具有不同临床行为的患者代谢簇。 PDAC 标本明显糖酵解，乳酸大量积累，在 106 名患者的较大队列中，将其作为胰液中的疾病特异性变量进行了探讨。在人 PDAC 切片中，葡萄糖转运蛋白 GLUT-1 的高表达与肿瘤分级和较高密度的 PD-1(+) T 细胞相关，表明它们在糖酵解肿瘤中积累。在临床前模型中，PD-1（+）CD8肿瘤浸润淋巴细胞差异性地浸润从具有不同代谢消耗的细胞系获得的PDAC肿瘤，并且通过敲低磷酸果糖激酶（Pfkm）基因进行代谢重新连接的肿瘤显示PD-1（+）细胞浸润减少。总的来说，我们将胰液作为代谢变量的宝贵来源，有助于鉴别诊断。代谢标志物与免疫浸润的相关性表明，对 PDAC 患者代谢特征的预先评估可以促进胰腺癌免疫治疗方法的引入。
Better understanding of pancreatic diseases, including pancreatic ductal adenocarcinoma (PDAC), is an urgent medical need, with little advances in preoperative differential diagnosis, preventing rational selection of therapeutic strategies. The clinical management of pancreatic cancer patients would benefit from the identification of variables distinctively associated with the multiplicity of pancreatic disorders. We investigated, by H-1 nuclear magnetic resonance, the metabolomic fingerprint of pancreatic juice (the biofluid that collects pancreatic products) in 40 patients with different pancreatic diseases. Metabolic variables discriminated PDAC from other less aggressive pancreatic diseases and identified metabolic clusters of patients with distinct clinical behaviors. PDAC specimens were overtly glycolytic, with significant accumulation of lactate, which was probed as a disease-specific variable in pancreatic juice from a larger cohort of 106 patients. In human PDAC sections, high expression of the glucose transporter GLUT-1 correlated with tumor grade and a higher density of PD-1(+) T cells, suggesting their accumulation in glycolytic tumors. In a preclinical model, PD-1(+) CD8 tumor-infiltrating lymphocytes differentially infiltrated PDAC tumors obtained from cell lines with different metabolic consumption, and tumors metabolically rewired by knocking down the phosphofructokinase (Pfkm) gene displayed a decrease in PD-1(+) cell infiltration. Collectively, we introduced pancreatic juice as a valuable source of metabolic variables that could contribute to differential diagnosis. The correlation of metabolic markers with immune infiltration suggests that upfront evaluation of the metabolic profile of PDAC patients could foster the introduction of immunotherapeutic approaches for pancreatic cancer.