Abstract
Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responded to TLR and growth factor stimulation and acted as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impaired antitumor immunity and accelerated tumor progression in murine models. Mechanistically, DYRK1A mediated the phosphorylation of the mTORC1 inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting the mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restored their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlated with effector T-cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A-TSC2-mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.
Authors
Hongjiao Wang, He Jiang, Songlin He, Songwen Ren, Haiwen Li, Wangnan Liu, Chunyun Zhou, Pan Zhu, Keren Chen, Weijia Cao, Yan Qin, Dan Du, Nengming Xiao, Hongling Huang, Chun-Jung Ko, Yiming Zheng, Bo Wang, Qiang Zou, Jian-Hong Shi, Xun Li, Zuliang Jie
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ISSN: 0021-9738 (print), 1558-8238 (online)