Intratumoral amino acid insufficiency limits CD8⁺ T-cell effector function

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Regulation

Background:

• CD8+ T-cells are crucial for anti-tumor immunity.
• Tumor-infiltrating CD8+ T-cells often lose effector function, limiting therapeutic efficacy.
• This dysfunction occurs despite sufficient cytotoxic protein transcripts, suggesting post-transcriptional regulation.

Purpose of the Study:

• To investigate the role of protein synthesis and amino acid availability in CD8+ T-cell dysfunction within the tumor microenvironment.
• To elucidate the mechanisms by which nutrient availability impacts T-cell function.

Main Methods:

• Analysis of mRNA translation rates in antigen-specific CD8+ T-cells from tumors and tumor-draining lymph nodes.
• Investigation of tRNA uncharging, integrated stress response, and mTORC1 signaling.
• Manipulation of glutaminase activity and amino acid transporter SLC6A15 expression.

Main Results:

• Intratumoral amino acid availability restricts CD8+ T-cell cytotoxic capacity by suppressing protein synthesis.
• mRNA translation rates were suppressed in tumor-infiltrating T-cells due to increased demand and reduced availability of amino acids.
• Amino acid-dependent tRNA uncharging suppressed protein synthesis independently of stress response or mTORC1.
• Restoring glutaminase activity or SLC6A15 expression rescued CD8+ T-cell effector function.

Conclusions:

• Nutrient availability in the tumor microenvironment is a critical determinant of CD8+ T-cell function.
• Altered amino acid metabolism and availability impair T-cell protein synthesis and anti-tumor immunity.
• Enhancing T-cell-specific amino acid availability represents a potential strategy to potentiate anti-tumor immunity.