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

Nina Cortese, Giovanni Capretti, Marialuisa Barbagallo, Alessandra Rigamonti, Panteleimon G Takis, Giovanni F Castino, Debora Vignali, Giulia Maggi, Francesca Gavazzi, Cristina Ridolfi, Gennaro Nappo, Greta Donisi, Marco Erreni, Roberta Avigni, Daoud Rahal, Paola Spaggiari, Massimo Roncalli, Paola Cappello, Francesco Novelli, Paolo MontiAlessandro Zerbi, Paola Allavena, Alberto Mantovani, Federica Marchesi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)493-505
Number of pages13
JournalCancer immunology research
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Aged
  • Animals
  • Biomarkers, Tumor/metabolism
  • CD8-Positive T-Lymphocytes/immunology
  • Carcinoma, Pancreatic Ductal/immunology
  • Cells, Cultured
  • Coculture Techniques
  • Female
  • Glucose Transporter Type 1/metabolism
  • Humans
  • Leukocytes, Mononuclear/immunology
  • Lymphocytes, Tumor-Infiltrating/immunology
  • Male
  • Metabolome
  • Mice
  • Mice, Transgenic
  • Pancreatic Juice/metabolism
  • Pancreatic Neoplasms/immunology
  • Programmed Cell Death 1 Receptor/immunology
  • Survival Rate

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