The following is a summary of “rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC,” published in the March 2024 issue of Oncology by Polcaro et al.
In the realm of non-small cell lung cancer (NSCLC) treatment, efficient predictive biomarkers to guide immune checkpoint inhibitor (ICI)-based immunotherapy are paramount. However, the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has yielded disparate outcomes. In this study, the objective was twofold: firstly, to ascertain the predictive validity of PD-L1 SNPs in advanced patients with NSCLC undergoing ICI treatment, and secondly, to elucidate the molecular mechanisms underpinning the influence of the identified SNP candidate. Among the SNPs examined, rs822336 emerged as a robust predictor of response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted patients with NSCLC, outperforming rs2282055 and rs4143815. Notably, rs822336 was found to reside within the promoter/enhancer region of PD-L1, exerting a differential impact on the induction of PD-L1 expression in human NSCLC cell lines.
Additionally, it influenced their susceptibility to human leukocyte antigen (HLA) class I antigen-matched peripheral blood mononuclear cells (PBMCs) following incubation with the anti-PD-1 monoclonal antibody nivolumab. Further exploration revealed that the induction of PD-L1 expression by rs822336 was mediated through a competitive allele-specific binding mechanism involving two identified transcription factors: CCAAT/enhancer-binding protein beta (C/EBPβ) and nuclear factor I/C (NFIC). Consequently, the silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines harboring distinct rs822336 genotypes.
The competitive allele-specificity binding of C/EBPβ and NFIC to the PD-L1 promoter/enhancer region based on rs822336 genotype was corroborated by binding microarray analysis in human NSCLC cell lines. These findings carry substantial clinical relevance, as they identify rs822336 and the induction of PD-L1 expression as novel biomarkers for predicting the efficacy of anti-PD-1/PD-L1-based immunotherapy in advanced patients with NSCLC.
Source: molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01976-2