Dataset Information

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1β.

ABSTRACT:

Introduction

Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC).

Methods

We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.

Results

The IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ.

Discussion

Our study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity.

SUBMITTER: Hirayama A

PROVIDER: S-EPMC10333574 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1β.

Hirayama Aiko A Tanaka Kentaro K Tsutsumi Hirono H Nakanishi Takayuki T Yamashita Sho S Mizusaki Shun S Ishii Yumiko Y Ota Keiichi K Yoneshima Yasuto Y Iwama Eiji E Okamoto Isamu I

Frontiers in immunology 20230627

<h4>Introduction</h4>Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC).<h4>Methods</h4>We performed comprehensive screening of cytokine gene expression in ...[more]

PMID: 37441079

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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:Background:The Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx and the Dako 28-8 IHC pharmDx assays were approved by the US Food and Drug Administration, as a companion diagnostic test for pembrolizumab (Keytruda, Merk, Kenilworth, NJ, USA) and a complementary diagnostic test for nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY, USA) in non-small cell lung cancer (NSCLC), respectively. Increased PD-L1 expression levels can be associated with greater therapeutic efficacy of pembrolizumab relative to other anti-PD-1 agents. However, in treatment decision making, little is known about which tissue (primary or metastatic lesion) should be stained by 22C3 antibody. We investigated the relationship between PD-L1 expression in primary tumors and paired metastatic lymph nodes using the 22C3 assay, and evaluated the concordance between the 22C3 and 28-8 assays. Methods:PD-L1 expression was evaluated in cells from primary tumors and paired metastatic lymph nodes using the 22C3 and 28-8 IHC assays. Total 35 patients with primary tumor and paired metastatic lymph node were enrolled into this study, and all samples were surgically resected, formalin-fixed, and paraffin-embedded NSCLC tissues. Tumor cells exhibiting complete or partial membrane staining, were considered as PD-L1 positive. On the basis of tumor proportion score (TPS), all samples were classified as no expression (TPS: <1%), low expression (TPS: 1-49%), or high expression (TPS: ?50%). Results:TPS distribution was markedly different between primary tumors and paired metastatic lymph nodes. In 22C3 IHC assay, TPS similar to that of metastatic lymph nodes was demonstrated in 10 primary tumors, and concordance rate between them was 28.6%. Concurrently, in 28-8 IHC assay, 11 primary tumors had TPS similar to that of metastatic lymph nodes, with a concordance rate of 31.4%. Conclusions:TPS concordance rates (for both 22C3 and 28-8 antibodies) between primary tumors and paired lymph nodes were low. Inter-tumor heterogeneity of PD-L1 expression is an important issue for clinical oncologists during treatment planning.

Dataset Information

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1β.

Introduction

Methods

Results

Discussion

Publications

Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1β.

Similar Datasets

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