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

Peng Liu (1, 2, 3) , Liwei Zhao (2, 1, 3) , Jonathan Pol (1, 2, 3) , Sarah Levesque (1, 2, 3) , Adriana Petrazzuolo (1, 2, 3) , Christina Pfirschke (4) , Camilla Engblom (4) , Steffen Rickelt (5) , Takahiro Yamazaki (6) , Kristina Iribarren (1, 2, 3) , Laura Senovilla (1, 2, 3) , Lucillia Bezu (1, 2, 3, 7) , Erika Vacchelli (1, 2, 3) , Valentina Sica (1, 2, 3) , Andréa Melis (8, 9) , Tiffany Martin (8, 9) , Xia Lin , Heng Yang , Qingqing Li , Jinfeng Chen , Sylvère Durand (10, 1, 2, 3) , Fanny Aprahamian (1, 2, 3) , Deborah Lefevre (1, 2, 3) , Sophie Broutin (1) , Angelo Paci (1) , Amaury Bongers (1) , Véronique Minard-Colin (1) , Eric Tartour (11, 3, 7) , Laurence Zitvogel (1, 12) , Lionel Apetoh (9, 8) , Yuting Ma , Mikael Pittet (4, 13) , Oliver Kepp (1, 2, 3) , Guido Kroemer (1, 2, 3, 14, 15)

1 IGR - Institut Gustave Roussy
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
3 USPC - Université Sorbonne Paris Cité
4 HMS - Harvard Medical School [Boston]
5 MIT - Massachusetts Institute of Technology
6 Weill Medical College of Cornell University [New York]
7 HEGP - Hôpital Européen Georges Pompidou [APHP]
8 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
9 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
10 MAP5 - UMR 8145 - Mathématiques Appliquées Paris 5
11 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
12 UMR 1015 - Immunologie des tumeurs et immunothérapie
13 Massachusetts General Hospital [Boston]
14 Karolinska University Hospital [Stockholm]
15 Service de biologie [CHU HEGP]

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.

Domaines: Pharmacologie; Cancer

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, 2019, 10, pp.1486. ⟨10.1038/s41467-019-09415-3⟩. ⟨hal-02098050⟩