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Nat Commun. 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.

Author information

1
Faculty of Medicine, University of Paris Sud, Kremlin-Bicêtre, 94270, France.
2
Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, 94805, France.
3
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, 75006, France.
4
Institut National de la Santé et de la Recherche Médicale, UMR1138, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, 75006, France.
5
Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France.
6
Université Pierre et Marie Curie, Paris, 75006, France.
7
Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, 02139, MA, USA.
8
Graduate Program in Immunology, Harvard Medical School, Boston, 02238, MA, USA.
9
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
10
Department of Radiation Oncology, Weill Cornell Medical College, New York, 14853, NY, USA.
11
Department of Anaesthesiology, Hôpital Européen Georges Pompidou, Paris, 75015, France.
12
Centre de Recherche INSERM LNC-, UMR1231, Dijon, France.
13
Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, 21000, France.
14
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
15
Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China.
16
Department of Pharmacology, Institut Gustave Roussy, Villejuif, 94805, France.
17
School of Pharmacy, Université Paris Sud, Châtenay-Malabry, 92 296, France.
18
Institut de Cancérologie, Gustave Roussy Cancer Campus (GRCC), Villejuif, 94805, France.
19
INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, Paris, 75006, France.
20
Department of Immunology, Hôpital Européen Georges Pompidou, Paris, 75015, France.
21
INSERM U1015, Villejuif, 94805, France.
22
Center of Clinical Investigations CIC1428, Villejuif, 94805, France.
23
Department of Radiology, Massachusetts General Hospital, Boston, 02114, MA, USA.
24
Faculty of Medicine, University of Paris Sud, Kremlin-Bicêtre, 94270, France. captain.olsen@gmail.com.
25
Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, 94805, France. captain.olsen@gmail.com.
26
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, 75006, France. captain.olsen@gmail.com.
27
Institut National de la Santé et de la Recherche Médicale, UMR1138, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, 75006, France. captain.olsen@gmail.com.
28
Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France. captain.olsen@gmail.com.
29
Université Pierre et Marie Curie, Paris, 75006, France. captain.olsen@gmail.com.
30
Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, 94805, France. kroemer@orange.fr.
31
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, 75006, France. kroemer@orange.fr.
32
Institut National de la Santé et de la Recherche Médicale, UMR1138, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, 75006, France. kroemer@orange.fr.
33
Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France. kroemer@orange.fr.
34
Université Pierre et Marie Curie, Paris, 75006, France. kroemer@orange.fr.
35
Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China. kroemer@orange.fr.
36
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France. kroemer@orange.fr.
37
Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, 141 86, Sweden. kroemer@orange.fr.

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.

PMID:
30940805
PMCID:
PMC6445096
DOI:
10.1038/s41467-019-09415-3
[Indexed for MEDLINE]
Free PMC Article

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