DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Area of Science:

• Molecular Biology
• Immunology
• Oncology

Background:

• RNA-binding proteins (RBPs) are crucial for cellular homeostasis, and their dysfunction is linked to cancer.
• The role of specific RBPs in tumor immune evasion via programmed death ligand-1 (PD-L1) regulation remains largely unknown.

Purpose of the Study:

• To identify RBPs involved in regulating PD-L1 expression and tumor immune evasion.
• To elucidate the mechanism by which DENR influences PD-L1 expression and anti-tumor immunity.

Main Methods:

• Targeted RNA-binding protein CRISPR/Cas9 screening was employed to identify PD-L1 regulators.
• In vitro and in vivo experiments assessed the impact of DENR depletion on PD-L1 expression, tumor growth, and CD8+ T cell activity.
• Mechanistic studies investigated the role of DENR in regulating JAK2 translation and the IFNγ-JAK-STAT signaling pathway.

Main Results:

• Density regulated re-initiation and release factor (DENR) was identified as a novel regulator of PD-L1.
• DENR depletion in cancer cells led to reduced PD-L1 expression both in vitro and in vivo.
• Suppression of DENR significantly inhibited tumor growth and augmented the anti-tumor efficacy of CD8+ T cells.
• DENR was found to antagonize translational repression of uORFs upstream of JAK2, impairing JAK2 translation and downstream signaling, ultimately reducing PD-L1.

Conclusions:

• DENR plays a critical role in regulating PD-L1 expression and mediating tumor immune evasion.
• Targeting DENR presents a promising therapeutic strategy for enhancing cancer immunotherapy by modulating the tumor immune microenvironment.