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: Molecular cancer Vol. 23; no. 1; p. 63
• Main Authors: Polcaro, Giovanna, Liguori, Luigi, Manzo, Valentina, Chianese, Annalisa, Donadio, Giuliana, Caputo, Alessandro, Scognamiglio, Giosuè, Dell'Annunziata, Federica, Langella, Maddalena, Corbi, Graziamaria, Ottaiano, Alessandro, Cascella, Marco, Perri, Francesco, De Marco, Margot, Col, Jessica Dal, Nassa, Giovanni, Giurato, Giorgio, Zeppa, Pio, Filippelli, Amelia, Franci, Gianluigi, Piaz, Fabrizio Dal, Conti, Valeria, Pepe, Stefano, Sabbatino, Francesco
• Format: Journal Article
• Language: English
• Published: England BioMed Central 25-03-2024; BMC
• Subjects: Alleles; Apoptosis; B7-H1 Antigen - genetics; Biomarkers; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; CCAAT-Enhancer-Binding Protein-beta - genetics; Cell death; Chemotherapy; Clinical medicine; Epidermal growth factor; Gene expression; Humans; Immune checkpoint inhibitors; Immunotherapy; Informed consent; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical prognosis; Metastasis; Molecular modelling; Monoclonal antibodies; NFI Transcription Factors; 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; United States > US; Germany; NSCLC; SNP; rs822336; Immunotherapy; PD-L1; PD-1; Predictive biomarker
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-024-01976-2

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.