Progranulin as a therapeutic target for immunomodulation in pancreatic ductal adenocarcinoma: role in chemoresistance
Final Report Abstract
Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Progranulin (protein: PGRN; gene: GRN), previously called granulin, granulin-epithelin precursor, or proepithelin, is a lysosomal protein that regulates autophagy in many diseases. In liver cancer, PGRN enhances the shedding of tumor cell MHC class I chain-related protein A (MICA), an innate NK and T cell stimulatory molecule, suggesting that PGRN might represent a tumorintrinsic factor rendering tumor cells insusceptible to immune elimination. In PDAC, the role of tumor-derived PGRN in immune evasion is largely unaddressed. In the study, we showed that tumor PGRN was a key instructive regulator of immune evasion by regulating MHCI via autophagy-lysosomal pathway in PDAC cells. In human PDAC, we revealed that PGRN exerted distinct functions on tumor cells and macrophages by transcriptomic analysis. Survival analysis showed that high PGRN expression in tumor cells, but not macrophages, predicted for poor survival and it was associated with CD8 infiltration in a negative manner. Further spatial imaging analysis using multiplex immunofluorescence (mIF) showed that high PGRN tumor expression was associated with low tumor MHCI expression and cytotoxic CD8 infiltration. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV- gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC, and identifies a new potential key mechanism exploited by PDAC cells for immune evasion. Following the published study, we continued working on the role of PGRN in Gemcitabine (GEM) resistance. 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 coculture experiments revealed that GEM treatment remarkably induced NK-mediated antitumor 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, we aims in the next step to delineate the underlying mechanism in the autophagymediated GzmB degradation in PDAC cells. The proposed project was approved as a renewal proposal for a research funding from DFG. 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 tumor microenvironment-based GEM resistance mechanism in PDAC patients and provide valuable information for the new combinatory treatment strategies of GEM and PGRN blockade.
Publications
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Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression. Nature Communications, 13(1).
Cheung, Phyllis F.; Yang, JiaJin; Fang, Rui; Borgers, Arianna; Krengel, Kirsten; Stoffel, Anne; Althoff, Kristina; Yip, Chi Wai; Siu, Elaine H. L.; Ng, Linda W. C.; Lang, Karl S.; Cham, Lamin B.; Engel, Daniel R.; Soun, Camille; Cima, Igor; Scheffler, Björn; Striefler, Jana K.; Sinn, Marianne; Bahra, Marcus ... & Siveke, Jens T.
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The 3rd Immuno-Oncology World Congress, Nov 2022, Copenhagen, Denmark. Tumor-Intrinsic Progranulin Drives Immune Evasion and Early Progression of Pancreatic Ductal Adenocarcinoma
Phyllis Fung-Yi Cheung
