Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent...

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Research

Background:

• Chronic lymphocytic leukemia (CLL) presents challenges for T-cell-based therapies due to T-cell dysfunction.
• Mitochondrial health is critical for T-cell function, but its role in CLL T-cell immunity is unclear.

Purpose of the Study:

• To investigate mitochondrial fitness in T cells from CLL patients.
• To explore metabolic and signaling alterations in CLL T cells.
• To assess the therapeutic potential of modulating T-cell metabolism for CLL treatment.

Main Methods:

• Integrated metabolic and functional analyses of T-cell subsets.
• Multiomics profiling (transcriptome, epigenome) of CLL T cells.
• Ex vivo and in vivo mouse models using CAR T-cell therapy and PI3K/Akt pathway inhibition.

Main Results:

• CLL T cells exhibit impaired, depolarized mitochondria across all subsets.
• Significantly altered mitochondrial signaling, reduced AMPK and autophagy, and upregulated glycolysis with Akt hyperactivation were observed.
• Inhibition of the PI3K/Akt pathway enhanced mitochondrial activity, memory differentiation, and CAR T-cell persistence and efficacy in a murine model.

Conclusions:

• Abnormal T-cell metabolism, characterized by mitochondrial dysfunction, contributes to therapeutic resistance in CLL.
• Modulating the PI3K/Akt pathway represents a promising strategy to enhance the efficacy of autologous T-cell therapies in CLL.