Crizotinib-induced immunogenic cell death in non-small cell lung cancer

Abstract : Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models. These anticancer effects are linked to increased T lymphocyte infiltration and are abolished by T cell depletion or interferon-γ neutralization. Crizotinib plus cisplatin leads to an increase in the expression of PD-1 and PD-L1 in tumors, coupled to a strong sensitization of NSCLC to immunotherapy with PD-1 antibodies. Hence, a sequential combination treatment consisting in conventional chemotherapy together with crizotinib, followed by immune checkpoint blockade may be active against NSCLC.
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Submitted on : Friday, April 12, 2019 - 12:38:53 PM
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Peng Liu, Liwei Zhao, Jonathan Pol, Sarah Levesque, Adriana Petrazzuolo, et al.. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nature Communications, Nature Publishing Group, 2019, 10, pp.1486. ⟨10.1038/s41467-019-09415-3⟩. ⟨hal-02098050⟩

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