期刊
BRITISH JOURNAL OF CANCER
卷 120, 期 5, 页码 527-536出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41416-018-0315-3
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资金
- FPRC ONLUS 5 x 1000, Ministero della Salute 2012
- Ricerca Finalizzata-Giovani Ricercatori Ministero della Salute [GR-2011-02349197]
- AIRC MFAG 2014 [15731]
- AIRC IG 2017 [20259]
- AIRC IG 2014 [15572]
- AIRC Special Program 5 x 1000 2010 MCO [9970]
- FPRC ONLUS 5 x 1000 Ministero della Salute 2011
- Italian Ministry of Health Ricerca Corrente 2017
- FPRC ONLUS 5 x 1000 Ministero della Salute 2013
- FPRC ONLUS 5 x 1000 Ministero della Salute 2014
BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-gamma modulation of PD-L1/PD-L2 in MET-amplified tumours. METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-gamma were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-gamma stimulation, and after anti-MET therapy. RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-gamma 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-gamma 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-gamma 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-gamma. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.
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