Abstract
BackgroundInterferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours.MethodsPD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy.ResultsPD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-γ treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/ STAT1, signal transducers downstream of the Interferon-γ receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-γ induced PD-L1 expression.ConclusionsThese data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-γ. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.
Highlights
Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion
IFNγ upregulates the expression of PD-1 ligands in MET-amplified tumours A panel of MET-amplified tumour cell lines from different tissue origins has been analysed for IFNγ-inducible PD-L1/PD-L2 expression
In the presence of IFNγ, MET-amplified tumour cells were more than 85% PD-L1 positive, with an increment in mean of fluorescence intensity (MFI) between 2 and 6 folds, depending on the cell line analysed (Fig. 1b, c)
Summary
Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. The presence of PD-L1 in several tumour types including lung, renal, gastric and ovarian cancer has been reported to negatively correlate with patients’ prognosis.[18,19,20,21,22] a predictive role of PD-L1 expression for clinical response to checkpoint inhibitors has been hypothesised by several studies It is currently accepted for lung cancer patients[8,23] but the threshold level or the applicability to other tumour types remains debated.[24,25] PD-L2 is a second PD-1 ligand, described to be expressed by tumour cells and components of tumour microenvironment.[26] Similar to PD-L1, PD-L2 is mainly regulated by interferons and endowed with the ability to inhibit T cell activity and proliferation. Its role in tumour immune-escape is not as well understood as compared with PD-L1 and currently PD-L2 blocking strategies are not approved in the clinic
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