Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Tumor immune evasion often involves inadequate Major Histocompatibility Complex class I (MHC-I) antigen presentation.
• Glycine decarboxylase (GLDC), an enzyme in glycine metabolism, is implicated in this process.

Purpose of the Study:

• To investigate the role of GLDC in regulating MHC-I expression and immune escape in EGFR-activated tumor cells.
• To elucidate the non-enzymatic mechanism by which GLDC suppresses MHC-I.

Main Methods:

• Investigated GLDC phosphorylation, nuclear translocation, and interaction with SMARCE1 in human non-small cell lung cancer (NSCLC) cells.
• Assessed the impact of GLDC on STAT1-dependent transcription of IRF1 and NLRC5.
• Examined GLDC recruitment of DNMT1 and subsequent DNA hypermethylation at the IRF1/NLRC5 promoter.
• Evaluated the effects of GLDC inhibition on MHC-I levels, CD8+ T cell function, and anti-tumor efficacy of PD-1 blockade in mouse models.

Main Results:

• EGFR activation leads to SRC-mediated phosphorylation and nuclear translocation of GLDC in NSCLC cells.
• Nuclear GLDC sequesters SMARCE1, inhibiting STAT1-dependent transcription of IRF1 and NLRC5.
• GLDC recruits DNMT1 to the IRF1/NLRC5 promoter, causing DNA hypermethylation and suppressing MHC-I gene expression.
• GLDC inhibition restored MHC-I levels, enhanced CD8+ T cell function within the tumor microenvironment, and improved anti-tumor responses to PD-1 blockade in mice.

Conclusions:

• GLDC possesses a non-enzymatic nuclear function that suppresses MHC-I antigen presentation, contributing to tumor immune escape.
• Targeting GLDC presents a novel strategy for enhancing immune checkpoint blockade (ICB) combination immunotherapy.