Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer

Antonio Agostini, Ilaria Guerriero, Geny Piro, Giuseppe Quero, Luca Roberto, Annachiara Esposito, Alessia Caggiano, Lorenzo Priori, Giulia Scaglione, Francesco De Sanctis, Antonella Sistigu, Martina Musella, Alberto Leonardo Larghi, Gianenrico Rizzatti, Donatella Lucchetti, Sergio Alfieri, Alessandro Sgambato, Emilio Bria, Laura Bizzozero, Sabrina ArenaStefano Ugel, Vincenzo Corbo, Giampaolo Tortora, Carmine Carbone

Risultato della ricerca: Contributo in rivistaArticolo in rivista


BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance.MethodsWe analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy.ResultsSpatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration.ConclusionsFinally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaJournal of Translational Medicine
Stato di pubblicazionePubblicato - 2023


  • Intraductal mucinous neoplasms (IPMNs)
  • Organoid interaction platform
  • Pancreatic ductal adenocarcinoma (PDAC)
  • Spatial transcriptomics
  • Syngeneic mouse models


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