Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways

Shiyu Bai; Qielan Wu; Shasha Zhu; Yuwei Zhang; Xuran Chen; Miya Su; Jun Pan; Shuhang Li; Ting Yue; Linfeng Xu; Di Xie; Chenxi Tian; Dan Zhao; Xiang Li; Junjie Hou; Lu Wang; Sicheng Fu; Yanhong Xue; Amin Jiang; Dong Li; Tao Xu; Zhigang Tian; Rongbin Zhou; Huimin Zhang; Li Bai

doi:10.3389/fimmu.2022.1051045

Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways

Front Immunol. 2023 Jan 19:13:1051045. doi: 10.3389/fimmu.2022.1051045. eCollection 2022.

Authors

Shiyu Bai^{1

2}, Qielan Wu^{1

2}, Shasha Zhu³, Yuwei Zhang^{1

2}, Xuran Chen^{1

2}, Miya Su^{1

2}, Jun Pan^{1

2}, Shuhang Li^{1

2}, Ting Yue⁴, Linfeng Xu⁴, Di Xie^{1

2}, Chenxi Tian^{1

2}, Dan Zhao², Xiang Li^{1

2}, Junjie Hou⁵, Lu Wang⁶, Sicheng Fu^{1

2}, Yanhong Xue⁵, Amin Jiang⁵, Dong Li⁵, Tao Xu⁵, Zhigang Tian^{1

2

4}, Rongbin Zhou^{1

2

4}, Huimin Zhang^{1

2}, Li Bai^{1

2

4

7

8}

Affiliations

¹ 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.
² School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁴ Biomedical Sciences and Health Laboratory of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁵ Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁶ Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁷ Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
⁸ National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China.

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: AMPK; Rab7a-Vam6-AMPK complex; Vam6; iNKT cells; mTORC1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Natural Killer T-Cells* / metabolism
Neoplasms*
Signal Transduction
TOR Serine-Threonine Kinases / metabolism
Vesicular Transport Proteins*

Substances

AMP-Activated Protein Kinases
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
VPS39 protein, mouse
Vesicular Transport Proteins

Grants and funding

This work was supported by National Key R&D Program of China 2021YFC2300604, National Natural Science Foundation of China 91954122, 92254304, 82071736, 82101912, 82202022, the CAS Project for Young Scientists in Basic Research (YSBR-074), Fundamental Research Funds for the Central Universities WK9110000149 and WK9100000001, the University Synergy Innovation Program of Anhui Province GXXT-2021-066, and the Natural Science Foundation of Hefei 2021024.