The role of IL-23/IL-23R axis in pancreatic ductal adenocarcinoma

• Applicant: Professorin Dr. Magdalena Huber
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553711594

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest solid malignancy with a 5-year overall survival of about 12% and a median overall survival rate of approximately 1 year. The standard chemotherapy includes gemcitabine or fluoropyrimidine-based combination and innovations have only marginally improved the survival probability over last years. Therefore, there is a need for an improved understanding of PDAC biology and for translation of findings obtained in basic research to new clinical approaches. Cytotoxic T lymphocytes (CTLs) are most efficient effectors in eradicating tumors and protecting from relapse, because of memory formation. However, PDAC is known to be poorly infiltrated by CTLs, which display a dysfunctional (exhausted) phenotype. Our preliminary data point to a crucial involvement of IL-23R expressed by CTLs in the steering CTL migration into PDAC tissue through the regulation of the CXCR6 chemokine receptor expression. In this proposal, we aim: (i) to characterize the IL-23R-dependent immune response in PDAC, (ii) to elucidate the mechanism of IL-23R-dependent regulation of CXCR6 expression by CTLs and (iii) to develop pre-clinical therapy strategies based on the regulation of CTL trafficking by IL-23R/IL-23 axis using orthtotopic PDAC mouse models. If successful, our data will lead to the development of new PDAC therapy regiments in the future, including a combinatory treatment with anti-IL-23 and anti-PD1 antibodies.

• DFG Programme: Research Grants