HuR up-regulates cell surface PD-L1 via stabilizing CMTM6 transcript in cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• CMTM6 stabilizes cell surface PD-L1 in cancer, crucial for immune evasion.
• Mechanisms regulating CMTM6 expression remain largely uncharacterized.

Purpose of the Study:

• To investigate the regulation of CMTM6 expression in cancer.
• To explore the functional consequences of CMTM6 regulation on PD-L1 levels and anti-tumor immunity.

Main Methods:

• Correlation analysis of CMTM6 and Hu-Antigen R (HuR) expression in cancer tissues.
• Investigating HuR's direct binding to CMTM6 mRNA using AU-rich elements (AREs) in the 3'UTR.
• Utilizing a HuR-specific inhibitor (MS-444) in cell culture and in vivo allograft models.
• Assessing PD-L1 expression, T cell activation (IL-2 production), and tumor progression.

Main Results:

• A strong positive correlation was observed between CMTM6 and HuR expression across various cancer types.
• HuR directly binds to CMTM6 mRNA's 3'UTR AREs, stabilizing it and increasing CMTM6 levels.
• HuR-high cancer cells exhibit elevated cell surface PD-L1, suppressing T cell activation (reduced IL-2).
• MS-444 treatment abolished HuR-mediated immune suppression and enhanced immune responses.
• Ectopic HuR accelerated tumor growth in vivo, an effect significantly reduced by MS-444.

Conclusions:

• HuR is a key regulator of CMTM6 expression, thereby controlling PD-L1 levels on cancer cells.
• Targeting HuR represents a potential therapeutic strategy to enhance anti-tumor immunity.
• Combining HuR inhibitors with PD-1/PD-L1 blockade may offer a novel approach for cancer immunotherapy.