Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• T cell dysregulation limits cancer immunotherapy success.
• Understanding T cell regulation is key to improving therapies like CAR-T and immune checkpoint blockade.

Purpose of the Study:

• Investigate the role of TRIM21 in regulating T cell function and anti-tumor immunity.
• Elucidate the molecular mechanism by which TRIM21 affects T cell activation.

Main Methods:

• Assessed TRIM21's impact on CD8+ T cell activation and anti-tumor immunity.
• Utilized Trim21 knockout (KO) models.
• Analyzed ubiquitination status of programmed cell death-1 (PD-1).

Main Results:

• TRIM21 impairs CD8+ T cell activation and anti-tumor immunity.
• TRIM21 catalyzes K63-linked ubiquitination of PD-1, stabilizing it.
• Trim21 KO decreased PD-1 expression, enhancing T cell activation and tumor sensitization to immunotherapy.
• Trim21 KO CAR-T cells showed improved anti-tumor efficacy.

Conclusions:

• TRIM21-mediated PD-1 stabilization restrains CD8+ T cell activation.
• Targeting the TRIM21-PD-1 axis is a potential strategy to enhance cancer immunotherapy.