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ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer

Oncogene (2024)Cite this article

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Abstract

Dendritic cells (DCs) are critical mediators of antigen priming and T-cell activation. Zymogen granule protein 16 (ZG16) is demonstrated as an anti-oncogene in T-cell mediated antitumor immunity, but its effect on DCs is largely unknown. Herein, we wonder whether ZG16 affects the activation of DCs in pancreatic cancer. Firstly, the increased ZG16 expression was observed during the maturation of DCs derived from mouse bone marrow or human peripheral blood. Then, overexpression of ZG16 or exogenous introduction of recombinant ZG16 protein induced the expression of MHC II, CD86, CD84, and CCR7 on the surface of DCs, thereby facilitating the secretion of proinflammatory mediators IL-1β, IL-6, TNF-α, and IL-12/p70, supporting the promoting effect of ZG16 on DC maturation. By establishing the subcutaneous and orthotopic mouse models of pancreatic cancer, we confirmed that intraperitoneal injection of recombinant ZG16 protein (Re-mZG16) could induce tumor regression by stimulating DC maturation and enhancing antitumor responses of CD4 + , CD8 + , PD-1 + , and Ctla4+ cells. Besides, Re-mZG16 in combination with gemcitabine showed a synergistic effect in the treatment of pancreatic cancer. Mechanistically, we demonstrated that ZG16 inhibited the ubiquitination and degradation of CD40, which depended on the lectin domain of ZG16. In conclusion, this study provided a novel insight into the role of ZG16-CD40 axis in DC-based immunotherapy for pancreatic cancer.

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Fig. 1: Effect of ZG16 on the maturation of mouse DCs.
Fig. 2: Effect of ZG16 on the maturation of human DCs.
Fig. 3: Effect of ZG16 on the expression of CD40.
Fig. 4: Role of CD40 in ZG16-induced DC maturation.
Fig. 5: Effect of Re-mZG16 protein combined with gemcitabine (GEM) on the growth of pancreatic cancer cells in vivo.
Fig. 6: Effect of Re-mZG16 protein treatment on the growth of in situ pancreatic cancer cells in mice.
Fig. 7: Effect of intra-tumoral (i.t.) injection of Ad-mZG16-DCs combined with gemcitabine (GEM) on the growth of pancreatic cancer cells in vivo.

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Data availability

The data used in this study will be made available from the corresponding author upon reasonable request.

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Funding

This study was supported by the Training Program for Young and Mid-Career Health Science and Technology Innovation Talents in Henan Province (Grant No. LJRC2023018) and the Natural Science Foundation of Henan Province in 2022 (Grant No. 232300420039).

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Author notes

  1. These authors contributed equally: Hui Meng, Ling Li.

Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China

    Hui Meng, Manman Nan, Yi Ding & Yizhen Li

  2. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China

    Ling Li & Mingzhi Zhang

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Contributions

HM: conceptualization, methodology, resources, writing – original draft; LL: data curation, investigation, formal analysis; MN: data curation, validation, visualization; YD: data curation, validation; YL: data curation, validation; MZ: resources, supervision, project administration, writing –review & editing.

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Meng, H., Li, L., Nan, M. et al. ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03154-6

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