High CD38 expression defines a mitochondrial function-adapted CD8⁺ T cell subset with implications for lung cancer...

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Specific CD8⁺ T cell subsets contribute to immunotherapy resistance, but underlying molecular mechanisms are unclear.
• CD38's role in CD8⁺ T cell function suggests its involvement in regulating T cell responses in lung cancer.

Purpose of the Study:

• To investigate the accumulation and function of CD38⁺CD8⁺ T cells in lung cancer.
• To explore the role of CD38⁺CD8⁺ T cells in resistance to immune checkpoint blockade (ICB) therapy.
• To evaluate therapeutic strategies targeting CD38 to overcome ICB resistance.

Main Methods:

• Phenotypic analysis of tumoral CD8⁺ T cells from lung cancer patients and preclinical models.
• Assessment of exhaustion markers, mitochondrial bioenergetics, and cytokine production (IFN-γ).
• Evaluation of combination therapy (PD-L1 mAbs and EGCG) in ICB-resistant murine lung cancer models.

Main Results:

• CD38⁺CD8⁺ T cells comprise CD38^hi and CD38^int subsets with heightened exhaustion markers and impaired mitochondrial function.
• Increased CD38^hiCD8⁺ T cells in the tumor microenvironment correlate with favorable anti-PD-1 therapy response in non-small-cell lung cancer.
• Combination therapy with PD-L1 mAbs and EGCG selectively reduced CD38^hiCD8⁺ T cells, enhanced IFN-γ, and improved survival in resistant models.

Conclusions:

• CD38-associated mitochondrial dysfunction drives CD8⁺ T cell exhaustion and intrinsic resistance to ICB therapy.
• Targeting CD38 offers a potential strategy to enhance PD-1 blockade efficacy in lung cancer.
• Restoring mitochondrial function in CD38^hiCD8⁺ T cells is crucial for regaining immunotherapy sensitivity.