Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours

Valentina Martin, Cristina Chiriaco, Chiara Modica, Anna Acquadro, Marco Cortese, Francesco Galimi, Timothy Perera, Loretta Gammaitoni, Massimo Aglietta, Paolo M Comoglio, Elisa Vigna, Dario Sangiolo

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Interferon-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.

METHODS: PD-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.

RESULTS: PD-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.

CONCLUSIONS: These 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.

Original languageEnglish
Pages (from-to)527-536
Number of pages10
JournalBritish Journal of Cancer
Volume120
Issue number5
DOIs
Publication statusPublished - Mar 2019

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Keywords

  • B7-H1 Antigen/drug effects
  • Cell Line, Tumor
  • Colorectal Neoplasms/pathology
  • Humans
  • Interferon-gamma/pharmacology
  • Janus Kinases/drug effects
  • Liver Neoplasms/secondary
  • Molecular Targeted Therapy
  • Neoplasms/genetics
  • Organoids
  • Programmed Cell Death 1 Ligand 2 Protein/drug effects
  • Protein Kinase Inhibitors/pharmacology
  • Proto-Oncogene Proteins c-met/antagonists & inhibitors
  • Receptors, Interferon
  • STAT1 Transcription Factor/drug effects
  • Signal Transduction
  • Tumor Escape/drug effects

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