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.

• Authors: Peng Liu, Liwei Zhao, Jonathan Pol, Sarah Levesque, Adriana Petrazzuolo, Christina Pfirschke, Camilla Engblom, Steffen Rickelt, Takahiro Yamazaki, Kristina Iribarren, Laura Senovilla, Lucillia Bezu, Erika Vacchelli, Valentina Sica, Andréa Melis, Tiffany Martin, Lin Xia, Heng Yang, Qingqing Li, Jinfeng Chen, Sylvère Durand, Fanny Aprahamian, Deborah Lefevre, Sophie Broutin, Angelo Paci, Amaury Bongers, Veronique Minard-Colin, Eric Tartour, Laurence Zitvogel, Lionel Apetoh, Yuting Ma, Mikael J Pittet, Oliver Kepp, Guido Kroemer
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1486 (04 02 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30940805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• Programmed Cell Death 1 Receptor
• Crizotinib
• Interferon-gamma

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• B7-H1 Antigen (genetics, immunology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, immunology, physiopathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Crizotinib (administration & dosage)
• Female
• Humans
• Interferon-gamma (immunology)
• Lung Neoplasms (drug therapy, genetics, immunology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Programmed Cell Death 1 Receptor (genetics, immunology)
• T-Lymphocytes (immunology)