CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer.
ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer.
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树突状细胞（DCs）是抗原提呈和T细胞活化的关键介质。酶原颗粒蛋白16（ZG16）已被证实在T细胞介导的抗肿瘤免疫中作为一种抑癌基因，但其对DCs的作用在很大程度上尚不清楚。
在此，我们探究ZG16是否影响胰腺癌中DCs的活化。首先，在来源于小鼠骨髓或人外周血的DCs成熟过程中观察到ZG16表达增加。随后，ZG16过表达或外源性引入重组ZG16蛋白诱导了DCs表面MHC II、CD86、CD84和CCR7的表达，从而促进促炎介质IL-1β、IL-6、TNF-α和IL-12/p70的分泌，支持ZG16对DC成熟的促进作用。通过建立胰腺癌皮下和原位小鼠模型，我们证实腹腔注射重组ZG16蛋白（Re-mZG16）可通过刺激DC成熟和增强CD4+、CD8+、PD-1+和Ctla4+细胞的抗肿瘤反应来诱导肿瘤消退。
此外，Re-mZG16联合吉西他滨在胰腺癌治疗中显示出协同效应。在机制上，我们证明ZG16抑制CD40的泛素化和降解，这依赖于ZG16的凝集素结构域。
总之，本研究为ZG16-CD40轴在基于DC的胰腺癌免疫治疗中的作用提供了新的见解。
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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