Progranulin as a therapeutic target for immunomodulation in pancreatic ductal adenocarcinoma: role in chemoresistance

• Applicant: Dr. Phyllis Fung-Yi Cheung, Ph.D.
• Subject Area: Gastroenterology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428311423

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with 5-year overall survival rate of 11%. Gemcitabine(GEM) remains a cornerstone for PDAC management, but the efficacy of GEM therapy is limited due to inherent or acquired resistance to GEM. While cell autonomous resistant mechanisms are well-documented, it is reported that tumor immune microenvironment also contributes to GEM resistance via release of immunostimulatory damage-associated molecular patterns(DAMPs) from dying tumor cells that could trigger immunogenic cell death(ICD). We demonstrated that progranulin (also called granulin, PGRN) was a key immunomodulator regulating tumor immune evasion via the lysosome-autophagy pathway. We therefore propose that PGRN might protect PDAC cells from DAMP-induced ICD mediated by cytotoxic cells and thus contributes to GEM resistance. Here we demonstrated in a PDAC patient cohort treated with GEM that high PGRN expression could predict overall and disease-free patient survival. In GEM-treated patient-derived xenograft models, higher PGRN expression of non-responding tumors was observed with low NK cell infiltration when compared to the partial responders. Ex vivo co-culture experiments revealed that GEM treatment remarkably induced NK-mediated anti-tumor cytotoxicity against PDAC cells with PGRN suppression. Notably, combination of PGRN blockade and GEM significantly prolonged survival in an aggressive spontaneous mouse model of PDAC with restored NK infiltration and cytotoxicity. Strikingly, a substantial level of GzmB signals in apoptotic tumors cells was only observed in the PGRN Ab-treated and combination-treated tumors, but not in single GEM-treated tumors. Previous study reported that increased autophagy could protect tumor cells from NK-mediated cytotoxicity by degrading GzmB via autophagy. Given the in vivo beneficial effect of PGRN blockade in sensitizing PDAC cells to GEM treatment, as well as the reported autophagy promoting role of PGRN, this project aims to delineate the underlying mechanism in the autophagy-mediated GzmB degradation in PDAC cells. The main objectives of this project are:1) study the role of PGRN blockade and GEM in promoting NK-mediated anti-tumor cytotoxicity via autophagy-dependent GzmB degradation pathway;2) address whether NK cells are the key effectors in the anti-tumor cytotoxicity induced by the combination treatment by In vivo NK depletion; and 3) investigate the clinical significance of PGRN, autophagy and NK cell infiltration in GEM-treated PDAC patients. With the proposed functional experiments, we aim to unravel a novel therapeutic aspect of PGRN blockade in sensitizing PDAC cells to GEM not only by activating NK cell activity, but also by disrupting the GEM resistance mechanism in PDAC cells by impairing GzmB degradation. The study will shed light on TME-based GEM resistance mechanism in PDAC patients and provide valuable information for the optimization of new combinatory treatment strategies.

• DFG Programme: Research Grants