Clinical implications of PD-L1 expression and pathway-related molecular subtypes in advanced Asian colorectal cancer patients

• Published in: American journal of cancer research 2024-01, Vol.14 (2), p.796-808
• Main Authors: Qiu, Qingqing, Tan, Dan, Chen, Qiaofeng, Zhou, Ru, Zhao, Xiaokai, Wen, Wei, Yang, Pengmin, Li, Jieyi, Gong, Ziying, Zhang, Daoyun, Wang, Mingliang
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 2156-6976; 2156-6976
• DOI: 10.62347/FSSF9938

The expression level of PD-L1 does not accurately predict the prognosis of advanced colorectal cancer (CRC) patients, but it still reflects the tumor microenvironment to some extent. By stratifying PD-L1 status, gene subtypes in PD-L1 positivity-related pathological pathways were analyzed for their relationship to MSI or TMB to provide more individualized treatment options for CRCs. A total of 752 advanced CRCs were included, and their genomic variance was measured by a targeted next generation sequencing panel in this study. MSI and TMB were both measured by NGS, while PD-L1 expression level was measured using the PD-L1 colon 22C3 pharmDx kit. We found RTK/RAS pathway was positively related to high PD-L1 expression, with and most mutations (G12 and G13) subtypes showing a significant correlation. Conversely, the Wnt and p53 pathways were negatively related to high PD-L1 expression, with C-terminal alterations and other non-inactivation mutations in making a primary contribution with significant statistical significance. Major subtypes showing a significantly higher proportion of TMB-H or MSI-H were irrespective of PD-L1 status. These findings demonstrate pathological pathways associated with high PD-L1 expression, suggesting that pathway-induced oncogenic constructive PD-L1 upregulation may be the reason for the corresponding patients' primary resistance to immune checkpoint inhibitors (ICIs), rather than a lack of pre-existing immune responses.