Metabolome of Pancreatic Juice Delineates Distinct Clinical Profiles of Pancreatic Cancer and Reveals a Link between Glucose Metabolism and PD-1+ Cells

胰腺癌 糖酵解 癌症研究 胰腺肿瘤 肿瘤微环境 医学 免疫系统 磷酸果糖激酶 腺癌 CD8型 内科学 生物 癌症 新陈代谢 免疫学
作者
Nina Cortese,Giovanni Capretti,Marialuisa Barbagallo,Alessandra Rigamonti,Panteleimon G. Takis,Giovanni Francesco Castino,Debora Vignali,G Maggi,Francesca Gavazzi,Cristina Ridolfi,Gennaro Nappo,Greta Donisi,Marco Erreni,Roberta Avigni,Daoud Rahal,Paola Scocco,Massimo Roncalli,Paola Cappello,Francesco Novelli,Paolo Monti,Alessandro Zerbi,Paola Allavena,Alberto Mantovani,Federica Marchesi
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:8 (4): 493-505 被引量:25
标识
DOI:10.1158/2326-6066.cir-19-0403
摘要

Abstract 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 1H 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.
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