The combination of gemcitabine and ginsenoside Rh2 enhances the immune function of dendritic cells against pancreatic cancer via the CARD9-BCL10-MALT1 / NF-κB pathway

Cold tumor immune microenvironment (TIME) of pancreatic cancer (PC) with minimal dendritic cell (DC) and T cell infiltration can result in insufficient immunotherapy and chemotherapy. While gemcitabine (GEM) is a first-line chemotherapeutic drug for PC, its efficacy is reduced by immunosuppression a...

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Published in:Clinical immunology (Orlando, Fla.) Fla.), 2023-03, Vol.248, p.109217-109217, Article 109217
Main Authors: Li, Qing, He, Jialuo, Li, Senlin, Tian, Cheng, Yang, Jian, Yuan, Huimin, Lu, Yi, Fagone, Paolo, Nicoletti, Ferdinando, Xiang, Ming
Format: Article
Language:English
Subjects:
Animals
B-Cell CLL-Lymphoma 10 Protein
CARD Signaling Adaptor Proteins - metabolism
CARD9-BCL10-MALT1/ NF-κB pathway
Cell Line, Tumor
Dendritic cell
Dendritic Cells
Gemcitabine
Ginsenoside Rh2
Immunity
Mice
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism
NF-kappa B - metabolism
Pancreatic cancer
Pancreatic Neoplasms
Tumor immune microenvironment
Tumor Microenvironment
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Summary:Cold tumor immune microenvironment (TIME) of pancreatic cancer (PC) with minimal dendritic cell (DC) and T cell infiltration can result in insufficient immunotherapy and chemotherapy. While gemcitabine (GEM) is a first-line chemotherapeutic drug for PC, its efficacy is reduced by immunosuppression and drug resistance. Ginsenoside Rh2 (Rh2) is known to have anti-cancer and immunomodulatory properties. Combining GEM with Rh2 may thus overcome immunosuppression and induce lasting anti-tumor immunity in PC. Here, we showed that after GEM−Rh2 therapy, there was significantly greater tumor infiltration by DCs. Caspase recruitment domain-containing protein 9 (CARD9), a central adaptor protein, was strongly up-regulated DCs with GEM−Rh2 therapy and promoted anti-tumor immune responses by DCs. CARD9 was found to be a critical target for Rh2 to enhance DC function. However, GEM−Rh2 treatment did not achieve the substantial anti-PC efficacy in CARD9−/− mice as in WT mice. The adoptive transfer of WT DCs to DC-depleted PC mice treated with GEM−Rh2 elicited strong anti-tumor immune responses, although CARD9−/− DCs were less effective than WT DCs. Our results showed that GEM−Rh2 may reverse cold TIME by enhancing tumor immunogenicity and decreasing the levels of immunosuppressive factors, reactivating DCs via the CARD9-BCL10-MALT1/ NF-κB pathway. Our findings suggest a potentially feasible and safe treatment strategy for PC, with a unique mechanism of action. Thus, Rh2 activation of DCs may remodel the cold TIME and optimize GEM chemotherapy for future therapeutic use. [Display omitted]
ISSN:1521-6616
1521-7035
DOI:10.1016/j.clim.2022.109217