Journal Article

rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC

Piaz, Fabrizio Dal, Conti, Valeria, Giurato, Giorgio, Filippelli, Amelia, Corbi, Graziamaria, Ottaiano, Alessandro, Liguori, Luigi, Cascella, Marco, Nassa, Giovanni, Caputo, Alessandro, Franci, Gianluigi, Pepe, Stefano, Dell’Annunziata, Federica, Perri, Francesco, De Marco, Margot, Chianese, Annalisa, Sabbatino, Francesco, Langella, Maddalena, Donadio, Giuliana, Manzo, Valentina, Scognamiglio, Giosuè, Zeppa, Pio, Col, Jessica Dal, Polcaro, Giovanna

2024

Overview

Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 ( PD-1 ) or its ligand 1 ( PD-L1 ) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1 , differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Alleles / Apoptosis / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell death / Chemotherapy / Clinical medicine / Epidermal growth factor / Gene expression / Immune checkpoint inhibitors / Immunotherapy / Informed consent / Kinases / Lung cancer / Medical prognosis / Metastasis / Molecular modelling / Monoclonal antibodies / Non-small cell lung carcinoma / NSCLC / Oncology / PD-1 / PD-1 protein / PD-L1 / PD-L1 protein / Predictive biomarker / Response rates / Single-nucleotide polymorphism / Small cell lung carcinoma / SNP / Transcription factors / Tumors / White people