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Scientific article
Open access
English

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

Published inNature Communications, vol. 10, no. 1, 1486
Publication date2019
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.

Keywords
  • 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
Affiliation Not a UNIGE publication
Citation (ISO format)
LIU, Peng et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. In: Nature Communications, 2019, vol. 10, n° 1, p. 1486. doi: 10.1038/s41467-019-09415-3
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Article (Published version)
Identifiers
ISSN of the journal2041-1723
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59downloads

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