Identification of CMTM6 and CMTM4 as PD-L1 protein regulators

Area of Science:

• Immunology
• Cancer Biology
• Molecular Cell Biology

Background:

• The PD-1/PD-L1 axis is crucial for suppressing anti-tumor T-cell responses in various metastatic cancers.
• While PD-L1 expression is key, its precise regulation remains poorly understood.
• Understanding PD-L1 regulation is vital for developing effective cancer immunotherapies.

Purpose of the Study:

• To identify novel regulators of Programmed Death-Ligand 1 (PD-L1) protein expression.
• To elucidate the mechanism by which identified regulators affect PD-L1 protein levels and function.
• To explore potential therapeutic strategies targeting PD-L1 regulation.

Main Methods:

• Conducted a haploid genetic screen to identify proteins regulating PD-L1.
• Utilized genetic modifier screens and complementation experiments.
• Investigated the effect of CMTM6 on PD-L1 transcription, ubiquitination, and protein half-life.
• Assessed the impact of CMTM6 on T-cell inhibition by PD-L1-expressing tumor cells.

Main Results:

• Identified CMTM6, a transmembrane protein, as a novel regulator of PD-L1 protein.
• CMTM6 and its family member CMTM4, but not other CMTMs, impair PD-L1 protein expression when interfered with.
• CMTM6 stabilizes PD-L1 by reducing its ubiquitination and increasing its half-life, without affecting transcription.
• CMTM6 enhances PD-L1-mediated inhibition of T-cell responses.

Conclusions:

• PD-L1 protein stability and function rely on regulation by CMTM6 and CMTM4.
• CMTM6 acts as a positive regulator of PD-L1 protein levels at the cell surface.
• Targeting CMTM6/4 interaction with PD-L1 presents a potential new strategy to block the PD-1/PD-L1 pathway in cancer.