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

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• mTORC1 activation is crucial for the anti-tumor functions of invariant natural killer T (iNKT) cells.
• The mechanisms causing impaired mTORC1 activation within tumor-infiltrating iNKT cells are not fully understood.

Purpose of the Study:

• To investigate the role of Vam6 in regulating mTORC1 activation and the function of intratumoral iNKT cells.
• To elucidate the molecular mechanisms by which Vam6 affects iNKT cell activity.

Main Methods:

• Generation of Vam6 mice.
• Flow cytometry and imaging approaches.
• RNA sequencing.

Main Results:

• Increased Vam6 expression in intratumoral iNKT cells correlates with impaired mTORC1 activation and reduced IFN-γ production.
• Vam6 facilitates the formation of a Rab7a-Vam6-AMPK complex, recruiting AMPK to lysosomes and activating it as an mTORC1 inhibitor.
• Vam6 counteracts VDAC1's inhibition of the Rab7a-Vam6-AMPK complex at mitochondria-lysosome contact sites.
• Tumor-derived lactic acid upregulates Vam6 expression in iNKT cells.

Conclusions:

• Vam6 negatively regulates mTORC1 activation and anti-tumor function in iNKT cells.
• Targeting Vam6 can restore iNKT cell-mediated anti-tumor immunity.
• Vam6 represents a potential therapeutic target for enhancing iNKT cell-based cancer immunotherapy.