Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression
Xinyuan Lei, Hsinyu Lin, Jieqi Wang, Zhanpeng Ou, Yi Ruan, Ananthan Sadagopan, Weixiong Chen, Shule Xie, Baisheng Chen, Qunxing Li, Jue Wang, Huayue Lin, Xiao‐Feng Zhu, Xiaoqing Yuan, Tian Tian, Xiaobin Lv, Sha Fu, Xiaorui Zhu, Jian Zhou, Guokai Pan, Xin Xia, Bakhos A. Tannous, Soldano Ferrone, Song Fan, Jinsong Li
Abstract
Mitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.