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

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Liu, Peng | Zhao, Liwei | Pol, Jonathan | Levesque, Sarah | Petrazzuolo, Adriana | Pfirschke, Christina | Engblom, Camilla | Rickelt, Steffen | Yamazaki, Takahiro | Iribarren, Kristina | Senovilla, Laura | Bezu, Lucillia | Vacchelli, Erika | Sica, Valentina | Melis, Andréa | Martin, Tiffany | Lin, Xia | Yang, Heng | Li, Qingqing | Chen, Jinfeng | Durand, Sylvère | Aprahamian, Fanny | Lefevre, Deborah | Broutin, Sophie | Paci, Angelo | Bongers, Amaury | Minard-Colin, Véronique | Tartour, Eric | Zitvogel, Laurence | Apetoh, Lionel | Ma, Yuting | Pittet, Mikael | Kepp, Oliver | Kroemer, Guido

Edité par CCSD ; Nature Publishing Group -

International audience. 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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