Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Regulation

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for hematological cancers but faces challenges in solid tumors.
• CD8+ T cell exhaustion is a key barrier limiting CAR-T cell efficacy in solid tumors.

Purpose of the Study:

• To investigate metabolic regulators contributing to CD8+ T cell exhaustion.
• To explore the therapeutic potential of targeting cystine metabolism in CAR-T cell therapy for solid tumors.

Main Methods:

• RNA sequencing to identify metabolic regulators in exhausted CD8+ T cells.
• Development and validation of a monoclonal antibody against SLC7A11.
• Single-cell RNA sequencing and functional assays to assess SLC7A11 inhibition effects.
• In vivo studies evaluating the impact of anti-SLC7A11 antibody on CAR-T cell antitumor efficacy.

Main Results:

• SLC7A11 was upregulated in exhausted CD8+ T cells.
• Inhibition of SLC7A11 promoted CD8+ stem-like memory T cell expansion and reduced T cell exhaustion.
• Treatment with an anti-SLC7A11 antibody enhanced CAR-T cell antitumor activity in vivo.
• SLC7A11 inhibition suppressed cystine uptake, activating the GCN2-eIF2α-SLC1A5 pathway, increasing glutamine uptake, and improving mitochondrial function.

Conclusions:

• Cystine restriction via SLC7A11 inhibition alleviates CD8+ T cell exhaustion.
• Targeting SLC7A11 represents a promising strategy to enhance CAR-T cell therapy for solid tumors.