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- Title
Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression.
- Authors
Lei, Xinyuan; Lin, Hsinyu; Wang, Jieqi; Ou, Zhanpeng; Ruan, Yi; Sadagopan, Ananthan; Chen, Weixiong; Xie, Shule; Chen, Baisheng; Li, Qunxing; Wang, Jue; Lin, Huayue; Zhu, Xiaofeng; Yuan, Xiaoqing; Tian, Tian; Lv, Xiaobin; Fu, Sha; Zhu, Xiaorui; Zhou, Jian; Pan, Guokai
- 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. Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.
- Subjects
MITOCHONDRIA; CANCER cells; MAJOR histocompatibility complex; T cell receptors; TUMOR antigens; T cells
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-31417-x