AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression
Xinyu Wang, Xinyu Wang, Yiyi Li, Yan Li, Xiumei Wang, Xiumei Wang, Hongrui Song, Yingzhao Wang, Chunliu Huang, Chengzhou Mao, Lixiang Wang, Cheng Zhong, Di Yu, Zijin Xia, Yongyi Feng, Jingjing Duan, Yujia Liu, Juanjuan Ou, Congzhou Luo, W.F. Mai, Hai Hong, Weibin Cai, Limin Zheng, Jean‐François Trempe, Edward A. Fon, Jing Liao, Yi Wei, Jun Chen
Abstract
The constrained cross-talk between myeloid cells and T cells in the tumor immune microenvironment (TIME) restricts cancer immunotherapy efficacy, whereas the underlying mechanism remains elusive. Parkin, an E3 ubiquitin ligase renowned for mitochondrial quality control, has emerged as a regulator of immune response. Here, we show that both systemic and macrophage-specific ablations of Parkin in mice lead to attenuated tumor progression and prolonged mouse survival. By single-cell RNA-seq and flow cytometry, we demonstrate that Parkin deficiency reshapes the TIME through activating both innate and adaptive immunities to control tumor progression and recurrence. Mechanistically, Parkin activation by AMP-activated protein kinase rather than PTEN-induced kinase 1 mediated major histocompatibility complex I down-regulation on macrophages via Autophagy related 5–dependent autophagy. Furthermore, Parkin deletion synergizes with immune checkpoint blockade treatment and Park2 −/− signature aids in predicting the prognosis of patients with solid tumor. Our findings uncover Parkin’s involvement in suppressing macrophage antigen presentation for coordinating the cross-talk between macrophages and T cells.