Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression
Year: 2022
Type: article
Abstract: Hypoexpression of human major histocompatibility complex (MHC) class I is widely known to be an important strategy of immune evasion in most cases of malignancies that lead to poor prognosis. We demonstrated that mitochondrial dynamics can be exploited as an efficient target in regulating MHC-I expression and cancer immunogenicity. Clinically, MHC-I expression and fragmentation of mitochondria are both closely associated to patient survival but are negatively correlated to one another. Mechanistically, it was observed that endoplasmic reticulum (ER) stress, an integrated signal transduction pathway activated in most rapidly proliferating tumor cells, played a crucial role in connecting mitochondrial fragmentation and cancer cell immunogenicity particularly via the IRE1α-XBP-1 s axis. XBP-1 s, which is activated by imbalanced mitochondrial fission and prolonged oxidative stress, served as a potent transcription factor, promoted the expression of aminopeptidase TPP2 and destructed the applicable antigenic peptide to impede MHC-I complex maturation and the activation of adaptive immune system upon cancer antigen. Our findings highlight the importance of mitochondrial dynamics in determining solid tumor immunogenicity and suggest that mediating mitochondrial fragmentation might provide a novel approach in anti-tumor immunotherapy.
Source: Nature Communications
Authors: Xinyuan Lei, Hsinyu Lin, Jieqi Wang, Zhanpeng Ou, Yi Ruan, Ananthan Sadagopan, Weixiong Chen, Shule Xie, Baisheng Chen, Qunxing Li, Jue Wang, Huayue Lin, Xiaofeng 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
Institutions: State University of New York, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Stony Brook University, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, Guangzhou University of Chinese Medicine, Guangzhou University, Longgang Central Hospital, Yale University, Nanjing Medical University, Nanchang University, University of Kentucky, Markey Cancer Center, Third Affiliated Hospital of Nanchang University, Third Hospital of Nanchang, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: G1860477862, G1878364232, Potential role of brachyury in HLA class I antigen processing machinery component downregulation in chordoma cells, T cell plasticity, fusion proteins and CAR T cell-based immunotherapy of head and neck cancer, G4119534169, G4606513410, G5304223692, B7-H3-SPECIFIC CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL IMMUNOTHERAPY FOR METASTATIC TRIPLE-NEGATIVE BREAST CANCER (MTNBC), ROLE OF THE HLA ANTIGEN PRESENTING MACHINERY (APM) IN RESISTANCE TO PD-1 AXIS BLOCKADE IN NON-SMALL CELL LUNG CANCER, G5850682332, G7448966117, G7517158600, Understanding and Overcoming Resistance to Cancer Immunotherapy Due to Defective Antigen Presentation, G8619980181, G8749632490
OpenAlex ID: W4283836999