Frontiers in Immunology (Jan 2023)
Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways
- Shiyu Bai,
- Shiyu Bai,
- Qielan Wu,
- Qielan Wu,
- Shasha Zhu,
- Yuwei Zhang,
- Yuwei Zhang,
- Xuran Chen,
- Xuran Chen,
- Miya Su,
- Miya Su,
- Jun Pan,
- Jun Pan,
- Shuhang Li,
- Shuhang Li,
- Ting Yue,
- Linfeng Xu,
- Di Xie,
- Di Xie,
- Chenxi Tian,
- Chenxi Tian,
- Dan Zhao,
- Xiang Li,
- Xiang Li,
- Junjie Hou,
- Lu Wang,
- Sicheng Fu,
- Sicheng Fu,
- Yanhong Xue,
- Amin Jiang,
- Dong Li,
- Tao Xu,
- Zhigang Tian,
- Zhigang Tian,
- Zhigang Tian,
- Rongbin Zhou,
- Rongbin Zhou,
- Rongbin Zhou,
- Huimin Zhang,
- Huimin Zhang,
- Li Bai,
- Li Bai,
- Li Bai,
- Li Bai,
- Li Bai
Affiliations
- Shiyu Bai
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Shiyu Bai
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Qielan Wu
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Qielan Wu
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Shasha Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Yuwei Zhang
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Yuwei Zhang
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Xuran Chen
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Xuran Chen
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Miya Su
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Miya Su
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Jun Pan
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Jun Pan
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Shuhang Li
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Shuhang Li
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Ting Yue
- Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Linfeng Xu
- Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Di Xie
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Di Xie
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Chenxi Tian
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Chenxi Tian
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Dan Zhao
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Xiang Li
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Xiang Li
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Junjie Hou
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Lu Wang
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Sicheng Fu
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Sicheng Fu
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Yanhong Xue
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Amin Jiang
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Dong Li
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Tao Xu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Zhigang Tian
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Zhigang Tian
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Zhigang Tian
- Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Rongbin Zhou
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Rongbin Zhou
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Rongbin Zhou
- Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Huimin Zhang
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Huimin Zhang
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Li Bai
- Department of Oncology of the First Affiliated Hospital, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Li Bai
- School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Li Bai
- Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Li Bai
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China
- Li Bai
- National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China
- DOI
- https://doi.org/10.3389/fimmu.2022.1051045
- Journal volume & issue
-
Vol. 13
Abstract
Activation of mTORC1 is essential for anti-tumor function of iNKT cells. The mechanisms underlying impaired mTORC1 activation in intratumoral iNKT cells remain unclear. Via generating Vam6+/- mice and using flow cytometry, image approach, and RNA sequencing, we studied the role of Vam6 in controlling mTORC1 activation and intratumoral iNKT cell functions. Here, we find that increased Vam6 expression in intratumoral iNKT cells leads to impaired mTORC1 activation and IFN-γ production. Mechanistically, Vam6 in iNKT cells is essential for Rab7a-Vam6-AMPK complex formation and thus for recruitment of AMPK to lysosome to activate AMPK, a negative regulator of mTORC1. Additionally, Vam6 relieves inhibitory effect of VDAC1 on Rab7a-Vam6-AMPK complex formation at mitochondria-lysosome contact site. Moreover, we report that lactic acid produced by tumor cells increases Vam6 expression in iNKT cells. Given the key roles of increased Vam6 in promoting AMPK activation in intratumoral iNKT cells, reducing Vam6 expression signifificantly enhances the mTORC1 activation in intratumoral iNKT cells as well as their anti-tumor effificacy. Together, we propose Vam6 as a target for iNKT cell-based immunotherapy.
Keywords
