Dataset Information

Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

ABSTRACT: Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD-1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and response to therapy. In this prospective observational study, plasma cytokine levels and PD-1, PD-L1 and PD-L2 expression was evaluated in circulating CD3+, CD3+CD4+ and CD3+CD8+ cells from 70 treatment-naïve patients with advanced NSCLC (Stage IIIB and IV) and from 10 healthy donors. The primary objective was to assess OS according to PD-1, PD-L1, PD-L2 expression status on PBMCs and lymphocyte subsets. Our results indicate that the percentage of PD-L1+CD3+, PD-L1+CD3+CD8+ PD-L2+PBMCs, PD-L2+CD3+, PD-L2+CD3+CD4+ cells was higher in patients than in healthy donors. Survival was decreased among patients with a high percentage of either PD-1+PBMCs, PD-1+CD3+, PD-L1+CD3+, PD-L1+CD3+CD8+, PD-L2+CD3+, PD-L2+CD3+CD4+, or PD-L2+CD3+CD8+ cells. IL-2 and TNF-? showed the strongest association with PD-L1 and PD-L2 expression on specific subsets of T-lymphocytes. Our findings suggest that increased PD-1/PD-L1/PDL-2 expression in PBMCs, particularly in T-cells, may be an additional mechanism leading to tumor escape from immune control. This study is registered with ClinicalTrials.gov, number NCT02758314.

SUBMITTER: Arrieta O

PROVIDER: S-EPMC5731930 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

Arrieta Oscar O Montes-Servín Edgar E Hernandez-Martinez Juan-Manuel JM Cardona Andrés F AF Casas-Ruiz Eibar E Crispín José C JC Motola Daniel D Flores-Estrada Diana D Barrera Lourdes L

Oncotarget 20171024 60

Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD-1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and respons ...[more]

PMID: 29254220

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Project description:BackgroundProgrammed cell death ligand-1 (PD-L1) and ligand-2 (PD-L2) interaction with programmed cell death protein-1 (PD-1) represent an immune-inhibiting checkpoint mediating immune evasion and is, accordingly, an important target for blockade-based immunotherapy in cancer. In non-small-cell lung cancer (NSCLC), improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted. Thus, in the present study, we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.MethodsWe performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression correlated genes in NSCLC. For this, we examined available datasets from the cancer cell line encyclopedia (CCLE) project lung non-small-cell (Lung_NSC) and the cancer genome atlas (TCGA) projects lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).ResultsAnalysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2. Moreover, we identified expression correlation between 489 genes and PD-L1, 191 genes and PD-L2, and 111 genes for both. PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC. In LUAD, we identified expression correlation between 257 genes and PD-L1, 914 genes and PD-L2, and 211 genes for both. In LUSC, we identified expression correlation between 26 genes and PD-L1, 326 genes and PD-L2, and 13 genes for both. Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets. Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC, for PD-L2 in LUSC, and for both PD-L1 and PD-L2 in LUAD. In LUSC, PD-L1, and to a lesser extent PD-L2, expression correlated with chromosome 9p24 localized genes, indicating a chromosome 9p24 topologically associated domain as an important driver of in particular LUSC PD-L1 expression. Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1 (PD-1), Cluster of differentiation 80 (CD80), and Repulsive guidance molecule B (RGMB) showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD. CD80 expression correlated with PD-L2 in LUSC.ConclusionsWe present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.

Project description:Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13-3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06-2.51, p = 0.024; HR 1.54 95% CI, 1.02-2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

Dataset Information

Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

Publications

Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

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