IL-27 mediates HLA class i up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

Carbotti, G. and Nikpoor, A. R. and Vacca, P. and Gangemi, R. and Giordano, C. and Campelli, F. and Ferrini, S. and Fabbi, M. (2017) IL-27 mediates HLA class i up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells. Journal of Experimental and Clinical Cancer Research, 36 (1).

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IL 27 mediates HLA class i up regulation which can be inhibited by the IL6 pathway in HLA deficient Small Cell Lung Cancer cells.pdf

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Abstract

Background: Recently, immunotherapy with anti-PD-1 antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC). Since anti-PD-1 re-activates anti-tumor Cytotoxic T Lymphocyte (CTL) responses, it is crucial to understand the mechanisms regulating HLA class I, and PD-L1 expression in HLA-negative SCLC. Here we addressed the role of IL-27, a cytokine related to both IL-6 and IL-12 families. Methods: The human SCLC cell lines NCI-N592, -H69, -H146, -H446 and -H82 were treated in vitro with different cytokines (IL-27, IFN-γ, IL-6 or a soluble IL-6R/IL-6 chimera sIL-6R/IL-6) at different time points and analyzed for tyrosine-phosphorylated STAT proteins by Western blot, for surface molecule expression by immunofluorescence and FACS analyses or for specific mRNA expression by QRT-PCR. Relative quantification of mRNAs was calculated by the ΔΔCT method. The Student's T test was used for the statistical analysis of experimental replicates. Results: IL-27 triggered STAT1/3 phosphorylation and up-regulated the expression of surface HLA class I antigen and of TAP1 and TAP2 mRNA in four out of five SCLC cell lines tested. The IL-27-resistant NCI-H146 cells showed up-regulation of HLA class I by IFN-γ. IFN-γ also induced expression of PD-L1 in SCLC cells, while IL-27 was less potent in this respect. IL-27 failed to activate STAT1/3 phosphorylation in NCI-H146 cells, which display a low expression of the IL-27RA and GP130 receptor chains. As GP130 is shared in IL-27R and IL-6R complexes, we assessed its functionality in response to sIL-6R/IL-6. sIL-6R/IL-6 failed to trigger STAT1/3 signaling in NCI-H146 cells, suggesting low GP130 expression or uncoupling from signal transduction. Although both sIL-6R/IL-6 and IL-27 triggered STAT1/3 phosphorylation, sIL-6R/IL-6 failed to up-regulate HLA class I expression, in relationship to the weak activation of STAT1. Finally sIL-6R/IL-6 limited IL-27-effects, particularly in NCI-H69 cells, in a SOCS3-independent manner, but did not modify IFN-γ induced HLA class I up-regulation. Conclusions: In conclusion, IL-27 is a potentially interesting cytokine for restoring HLA class I expression for SCLC combined immunotherapy purposes. However, the concomitant activation of the IL-6 pathway may limit the IL-27 effect on HLA class I induction but did not significantly alter the responsiveness to IFN-γ. © 2017 The Author(s).

Item Type: Article
Additional Information: Cited By :7 Export Date: 16 February 2020 CODEN: JECRD Correspondence Address: Ferrini, S.; Ospedale Policlinico San Martino, IRCCS for OncologyItaly; email: silvano.ferrini@libero.it
Uncontrolled Keywords: HLA class I IL-27 IL-6 PD-L1 Small Cell Lung Cancer SOCS3 STAT1/3 gamma interferon HLA antigen class 1 interleukin 12 interleukin 27 interleukin 6 interleukin 6 receptor messenger RNA programmed death 1 ligand 1 STAT protein STAT1 protein biological marker glycoprotein gp 130 protein binding STAT3 protein Article controlled study gene gene expression human human cell IL6RA gene in vitro study lung cancer cell line priority journal protein expression protein function protein phosphorylation signal transduction TAP1 gene TAP2 gene upregulation gene expression regulation genetics immunology immunotherapy lung tumor metabolism tumor cell line Biomarkers Cell Line, Tumor Cytokine Receptor gp130 Gene Expression Regulation, Neoplastic Histocompatibility Antigens Class I Humans Interleukin-27 Interleukin-6 Lung Neoplasms Small Cell Lung Carcinoma STAT1 Transcription Factor STAT3 Transcription Factor
Subjects: WF Respiratory System
QU Biochemistry
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib3 lib3
Date Deposited: 18 May 2020 09:07
Last Modified: 18 May 2020 09:07
URI: http://eprints.mums.ac.ir/id/eprint/16786

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