Dataset Information

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

ABSTRACT:

Introduction

Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed.

Materials and methods

The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation between ROS1 fusion and PD-L1 expression, we down-regulated ROS1 with RNA interference or specific inhibitor (Crizotinib) in ROS1-fusion positive NSCLC cell line HCC78; or up-regulate ROS1-fusion gene in an immortalized human bronchial epithelial cell line (HBE). Mouse xenograft models were also used to determine the effect of ROS1 expression on PD-L1 expression in vivo. Crizotinib-resistant cell line was generated for measuring the association between Crizotinib resistance and PD-L1 expression.

Results

ROS1-rearrangement in primary NSCLC tumor was significantly associated with up-regulated PD-L1 expression. PD-L1 expression was significantly up-regulated in bronchial epithelial cells after forced expression of ROS1 fusion and was eliminated when HCC78 xenograft mouse models were treated with Crizotinib. We found PD-L1 expression was modulated by MEK-ERK pathway signaling in both parental and Crizotinib-resistant NSCLC cells with ROS1 fusion.

Conclusions

The correlation between ROS1-fusion and PD-L1 overexpression suggested that PD-L1/PD-1 blockade could be the second-line treatment option for the Crizotinib-resistant NSCLC with ROS1 rearrangement.

SUBMITTER: Liu Z

PROVIDER: S-EPMC7458663 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

Liu Zheng Z Zhao Kejia K Wei Shiyou S Liu Chengwu C Zhou Jiankang J Gou Qiheng Q Wu Xia X Yang Zhenyu Z Yang Yanbo Y Peng Yong Y Cheng Qing Q Liu Lunxu L

Oncoimmunology 20200506 1

<h4>Introduction</h4>Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed.<h4>Materials and methods</h4>The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation ...[more]

PMID: 32923114

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Project description:Introduction: The PD-1/PD-L1 axis is hijacked by lung adenocarcinoma (LUAD) cells to escape immune surveillance. PD-L1 expression in LUAD is affected, among others, by the metabolic trafficking between tumor cells and the tumor microenvironment (TME). Methods: Correlation between PD-L1 expression and iron content within the TME was established on FFPE LUAD tissue samples. The effects of an iron rich microenvironment on PD-L1 mRNA and protein levels were assessed in vitro in H460 and A549 LUAD by using qPCR, western blot and flow citometry. c-Myc knockdown was performed to validate the role of this transcription factor on PD-L1 expression. The effects of iron-induced PD-L1 on T cell immune function was assessed by quantifying IFN-γ release in a co-colture system. TCGA dataset was used to analyse the correlation between PD-L1 and CD71 mRNA expression in LUAD patients. Results: In this study, we highlight a significant correlation between iron density within the TME and PD-L1 expression in 16 LUAD tissue specimens. In agreement, we show that a more pronounced innate iron-addicted phenotype, indicated by a higher transferrin receptor CD71 levels, significantly correlates with higher PD-L1 mRNA expression levels in LUAD dataset obtained from TCGA database. In vitro, we demonstrate that the addition of Fe3+ within the culture media promotes the significant overexpression of PD-L1 in A549 and H460 LUAD cells, through the modulation of its gene transcription mediated by c-Myc. The effects of iron lean on its redox activity since PD-L1 up-regulation is counteracted by treatment with the antioxidant compound trolox. When LUAD cells are co-cultured with CD3/CD28-stimulated T cells in an iron-rich culture condition, PD-L1 up-regulation causes the inhibition of T-lymphocytes activity, as demonstrated by the significant reduction of IFN-γ release. Discussion: Overall, in this study we demonstrate that iron abundance within the TME may enhance PD-L1 expression in LUAD and, thus, open the way for the identification of possible combinatorial strategies that take into account the iron levels within the TME to improve the outcomes of LUAD patients treated with anti-PD-1/PD-L1-based therapies.

Dataset Information

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

Introduction

Materials and methods

Results

Conclusions

Publications

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

Similar Datasets

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