CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport

ABSTRACT

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9^−/− DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.

KEYWORDS:

• CARD9
• creatine
• dendritic cells
• pancreatic cancer
• SLC6A8

Author contributions

Ming Xiang participated in the study design, material support, coordination, and supervision of the study. Cheng Tian, Huimin Yuan, and Yi Lu designed the experimental validation, performed experiments, analyzed the data, and drafted the manuscript. Henghui He, Qing Li., Senlin Li, Jian Yang, Mengheng Wang, and Ruochen Xu carried out parts of the experiments and provided constructive discussion about experiments. Qian Liu provided effective work direction. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available from M.X. upon reasonable request.

Ethics approval and consent to participate

Animal care and experimental procedures were carried out in accord with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2204015.

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [81872000].