Crizotinib-induced immunogenic cell death in non-small cell lung cancer - Published on 06 06 2019
2019 Apr 2;10(1):1486. doi: 10.1038/s41467-019-09415-3.

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

Liu P1,2,3,4,5,6, Zhao L1,2,3,4,5,6, Pol J2,3,4,5,6, Levesque S1,2,3,4,5,6, Petrazzuolo A1,2,3,4,5,6, Pfirschke C7, Engblom C7,8, Rickelt S9, Yamazaki T10, Iribarren K2,3,4,5,6, Senovilla L2,3,4,5,6, Bezu L1,2,3,4,5,6,11, Vacchelli E2,3,4,5,6, Sica V2,3,4,5,6, Melis A12,13, Martin T12,13, Xia L14,15, Yang H14,15, Li Q14,15, Chen J14,15, Durand S2,3,4,5,6, Aprahamian F2,3,4,5,6, Lefevre D2,3,4,5,6, Broutin S16, Paci A16,17, Bongers A16, Minard-Colin V18, Tartour E19,20, Zitvogel L1,15,18,21,22, Apetoh L12,13, Ma Y14,15, Pittet MJ7,23, Kepp O24,25,26,27,28,29, Kroemer G30,31,32,33,34,35,36,37.


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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