Journal Article

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

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

2019

Overview

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. Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/2 / 14 / 49 / 49/47 / 49/98 / 631/250/1933 / 631/67/1059/2325 / 631/67/1059/602 / 631/80/39 / 631/80/82 / Animals / Antibodies / Anticancer properties / Antineoplastic Agents - administration & dosage / Antitumor activity / Apoptosis / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Cancer / Carcinogens / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - physiopathology / Cell death / Cell Death - drug effects / Cell Line, Tumor / Chemotherapy / Cisplatin / Crizotinib - administration & dosage / Depletion / Enzyme inhibitors / Female / Humanities and Social Sciences / Humans / Immune checkpoint / Immunogenicity / Immunotherapy / Infiltration / Inhibitor drugs / Interferon / Interferon-gamma - immunology / Kinases / Life Sciences / Lung cancer / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - immunology / Lung Neoplasms - physiopathology / Lung transplantation / Lymphocytes / Lymphocytes T / Metastases / Mice / Mice, Inbred C57BL / Mortality / multidisciplinary / Neutralization / Non-small cell lung carcinoma / PD-1 protein / PD-L1 protein / Pharmaceutical sciences / Pharmacology / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Protein-tyrosine kinase / Science / Science (multidisciplinary) / Small cell lung carcinoma / T-Lymphocytes - immunology / Targeted cancer therapy / Tumors / Tyrosine / γ-Interferon