The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Immune checkpoint inhibitors (ICIs) show efficacy in mismatch repair-deficient (MMRd) cancers.
• Approximately 50% of MMRd cancer patients exhibit resistance to ICIs.
• Differential regulation of response factors upon MMR gene loss is a potential cause of resistance.

Purpose of the Study:

• Investigate the impact of distinct MMR gene loss on factors influencing ICI response.
• Elucidate the novel regulatory role of MSH6 in PD-L1 transcription.
• Examine the relationship between MMR gene status, microsatellite instability, and mutational burden.

Main Methods:

• Analysis of PD-L1 expression in MMR gene knockout (KO) cancer cells.
• Investigating MSH6's role in PD-L1 transcription via SETD2 recruitment.
• Next-generation sequencing (NGS) of MLH1 and MSH6 KO cells to assess microsatellite instability and mutational burden.

Main Results:

• Loss of MLH1, MSH2, and PMS2 correlates with increased PD-L1 expression.
• MSH6 loss does not increase PD-L1 expression due to MSH6's direct transcriptional regulation of PD-L1.
• MSH6 KO cells exhibit lower microsatellite instability than MLH1 KO cells, despite higher mutational burden.

Conclusions:

• MSH6 acts as a direct regulator of PD-L1 transcription, dependent on SETD2.
• Gene-specific stratification within the MMRd cancer cohort is crucial for predicting ICI response.
• Understanding MMR gene function is key to overcoming ICI resistance.