Mitochondrial impairment and mTORC1 signalling exhaustion define NK Cell dysfunction progression in melanoma

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Research

Background:

• Cutaneous melanoma is a metastatic cancer with limited treatment options.
• Immune checkpoint inhibitors (ICI) benefit only about 50% of patients.
• Natural killer (NK) cells are crucial for anti-cancer immunity but can become dysfunctional during cancer progression.

Purpose of the Study:

• To investigate the metabolic and functional changes in circulating NK cells during melanoma progression (Stage III vs. Stage IV).
• To explore the potential for therapeutic intervention by assessing NK cell metabolic plasticity.

Main Methods:

• Analysis of circulating NK cells from Stage III and Stage IV melanoma patients.
• Assessment of mitochondrial mass, morphology, mTORC1 activity, and cytokine responsiveness.
• Pharmacologic intervention with MHY1485 to restore mTORC1 activity and assess IFN-γ production.

Main Results:

• Stage III NK cells showed reduced mitochondrial mass, impaired morphology, dysregulated mTORC1, and reduced cytotoxicity.
• Stage IV NK cells exhibited severe mitochondrial fragmentation, altered mTORC1, and diminished cytokine response.
• MHY1485 restored IFN-γ in Stage III NK cells but not in Stage IV, indicating stage-dependent metabolic responsiveness.

Conclusions:

• Circulating NK cells undergo progressive metabolic and functional impairment with advancing melanoma.
• Therapeutic strategies targeting NK cell metabolism earlier in disease progression may be more effective.
• Understanding NK cell plasticity is key for developing novel immunotherapies for melanoma.