AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression
Menée in vitro et à l'aide de modèles murins de tumeur, cette étude met en évidence un mécanisme par lequel l'activation de la parkine (une ubiquitine ligase E3) favorise la progression tumorale en supprimant la présentation de l'antigène par les macrophages associés à la tumeur
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. Parkin suppresses antigen presentation in tumor-associated macrophage via degradation of MHC-I through autophagy.
Science Advances 2024