Abstract
BackgroundRecently, 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.MethodsThe 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.ResultsIL-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.ConclusionsIn 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.
Highlights
Immunotherapy with anti-Programmed Death-1 (PD-1) antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC)
IL-27 up-regulates surface Human Leukocyte Antigen (HLA) class I expression in SCLC cells In view of the defective expression of HLA class I molecules in SCLC [9], we tested whether IL-27 could upregulate membrane HLA, as recently reported in other tumor cell types [18]
Previous clinical studies showed that IFN-γ therapy has no impact on survival in patients with SCLC in remission after standard therapies [51, 52] and this finding may relate to the ability of IFN-γ to induce immune-resistance through the Programmed Death-Ligand 1 (PD-L1)/PD-1 pathway
Summary
Immunotherapy with anti-PD-1 antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC). Small Cell Lung Cancer (SCLC) is an aggressive tumor characterized by rapid and extensive metastatic dissemination, recurrence after chemotherapy and poor prognosis. A recent phase I-II trial of the anti-PD-1 antibody nivolumab in patients with recurrent SCLC showed a 10% response rate and a 32% disease control rate [5]. Different schedules of nivolumab in combination with ipilimumab showed 19–23% response rates [5]. These results prompted the National Comprehensive Cancer Network to consider the nivolumab-ipilimumab combination in the 2016 guidelines for SCLC treatment
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