Impact of copy number variant and single nucleotide polymorphism of the programmed death‑ligand 1 gene, programmed death‑ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non‑small cell lung carcinoma

Abstract

Anti-programmed death-1 or anti-programmed death-ligand 1 (PD-L1) blockade may be ineffective in some patients with non-small cell lung cancer (NSCLC) with high percentage of tumor cells with PD-L1 expression. In addition, immunotherapy may provide great benefits in patients without PD-L1 expression. The present study assessed PD-L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD-L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD-L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD-L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD-L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD-L1 expression compared to patients with lower percentage of PD-L1-positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD-L1 copies and percentage of tumor cells with PD-L1 protein expression. Percentage of tumor cells with PD-L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P= 0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120-3.0490). The present study demonstrated a close relationship between

Common inherited variants of PDCD1, CD274 and HAVCR2 genes differentially modulate the risk and prognosis of adenocarcinoma and squamous cell carcinoma

“…This haplotype had T allele at rs822335 in addition to allele A at rs2297136. The impact of rs822335 on PD-L1 expression was investigated in tissue samples of NSCLC patients by Krawczyk et al ( 2019 ) and Grenada et al ( 2021 ). These authors detected a higher percentage of tumour cells presenting PD-L1 assessed by IHC in samples from patients with CC genotype compared to CT or TT genotypes (Krawczyk et al 2019 ; Grenda et al 2021 ).…”

“…The impact of rs822335 on PD-L1 expression was investigated in tissue samples of NSCLC patients by Krawczyk et al ( 2019 ) and Grenada et al ( 2021 ). These authors detected a higher percentage of tumour cells presenting PD-L1 assessed by IHC in samples from patients with CC genotype compared to CT or TT genotypes (Krawczyk et al 2019 ; Grenda et al 2021 ). We carried out in silico analysis with RegulomeDB and 3DSNP 2.0 databases which showed that rs822335 was annotated with the enhancer state in the A549 cell line and Lung Fibroblast Primary Cells (NHLF), however, any potential binding site for transcription factor related to rs822335 was revealed.…”

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

“…For instance, a significant correlation between C/C genotype and OS in NSCLC patients is reported by Zhao et al as well as by Kang et al [ 69 , 70 ]. In contrast, no significant difference in survival outcomes based on rs822336 genotype is reported [ 48 , 71 , 72 ]. Here, we do not analyze the prognostic role of PD-L1 SNPs.…”