Reversible control of T cell exhaustion by NR4A transcription factors revealed through targeted protein degradation

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Tumor-infiltrating CD8+ T cells (TILs) often lose function and gain inhibitory receptors, contributing to immune evasion.
• NR4A transcription factors are identified as key regulators driving this T cell dysfunction and exhaustion.

Purpose of the Study:

• To investigate the role of NR4A transcription factors in T cell dysfunction.
• To develop a therapeutic strategy for restoring anti-tumor function by targeting NR4A proteins.

Main Methods:

• Development of degron-based systems for rapid degradation of endogenous NR4A proteins in mouse and human T cells.
• Transcriptional profiling of phenotypically defined T cell populations.
• CRISPR-mediated gene editing combined with small molecule degraders in primary human CD8+ T cells.

Main Results:

• Continuous presence of NR4A proteins is necessary for suppressing effector cytokines and maintaining co-inhibitory receptor expression.
• Degradation of individual NR4A proteins rapidly restored T cell effector functions, impacting distinct and overlapping gene subsets.
• Targeted NR4A degradation maintained cytokine expression and suppressed inhibitory receptors in chronically stimulated human T cells.

Conclusions:

• Individual NR4A family members contribute to T cell dysfunction through both shared and unique mechanisms.
• Targeted degradation of NR4A proteins represents a viable therapeutic strategy to restore anti-tumor T cell function.