: 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.

rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC / 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. - In: MOLECULAR CANCER. - ISSN 1476-4598. - 23:1(2024). [10.1186/s12943-024-01976-2]

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

Donadio, Giuliana;Caputo, Alessandro;Corbi, Graziamaria;Perri, Francesco;Zeppa, Pio;Filippelli, Amelia;Franci, Gianluigi;Conti, Valeria;Pepe, Stefano;Sabbatino, Francesco
2024

Abstract

: 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.
2024
rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC / 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. - In: MOLECULAR CANCER. - ISSN 1476-4598. - 23:1(2024). [10.1186/s12943-024-01976-2]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/957652
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