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CARD9 缺陷通过 SLC6A8 介导的肌酸转运阻断树突状细胞成熟从而促进胰腺癌生长。

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

机构信息

Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

出版信息

Oncoimmunology. 2023 Apr 19;12(1):2204015. doi: 10.1080/2162402X.2023.2204015. eCollection 2023.

DOI:10.1080/2162402X.2023.2204015
PMID:37089447
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10120541/
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.

摘要

胰腺癌（PC）的存活率低，预后差。在此，我们发现半胱氨酸天冬氨酸蛋白酶募集域蛋白 9（CARD9）的表达与 PC 患者的预后呈正相关，CARD9 主要在先天免疫细胞中表达。CARD9 缺陷型 PC 小鼠表现出更快的癌症进展和更差的生存率。CARD9 敲除降低了树突状细胞（DC）的成熟度，并损害了 DC 在体内和体外激活 T 细胞的能力。树突状细胞转移实验证实了 CARD9 缺失在 PC 中的作用依赖于 DC。肌酸被鉴定为 WT DC 和 CARD9 DC 之间差异最显著的代谢物，它在维持 DC 成熟和功能方面起着重要作用。CARD9 缺陷通过抑制肌酸特异性转运蛋白溶质载体家族 6 成员 8（SLC6A8）的转录，导致 DC 中的肌酸水平降低。进一步的研究表明，CARD9 缺失通过消除 CARD9-BCL10-MALT1 复合物的形成，阻止了 p65 与 SLC6A8 启动子的结合，从而阻止了 p65 的激活。这些事件减少了肌酸向 DC 的转运，导致 DC 不成熟和抗肿瘤免疫功能受损，进而促进 PC 的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/6ce2e8b21e7e/KONI_A_2204015_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/2b341138bf6c/KONI_A_2204015_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/510d7a1c0686/KONI_A_2204015_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/58684d017c0b/KONI_A_2204015_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/e136e59979a8/KONI_A_2204015_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/2ee6e2af0bec/KONI_A_2204015_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/ff5cf8b84d35/KONI_A_2204015_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/a0aa9aadc198/KONI_A_2204015_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/6ce2e8b21e7e/KONI_A_2204015_F0008_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/2b341138bf6c/KONI_A_2204015_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/510d7a1c0686/KONI_A_2204015_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/58684d017c0b/KONI_A_2204015_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/e136e59979a8/KONI_A_2204015_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/2ee6e2af0bec/KONI_A_2204015_F0005_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/ff5cf8b84d35/KONI_A_2204015_F0006_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/a0aa9aadc198/KONI_A_2204015_F0007_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5a7/10120541/6ce2e8b21e7e/KONI_A_2204015_F0008_OC.jpg

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