期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09415-3
关键词
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资金
- Ligue contre le Cancer Comite de Charente-Maritime (equipe labelisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Ligue contre le Cancer Comite de Charente-Maritime
- China Scholarship Council
- Horizon 2020/European Union (Alkatraz)
- MGH ECOR Tosteson Postdoctoral Fellowship
- Metastasis/Cancer Research Postdoc fellowship from the MIT Ludwig Center for Molecular Oncology Research
- NIH [U54-CA163109]
- Howard Hughes Medical Institute
- Natural Science Foundation of China (NSFC) [81722037, 81671630]
- China Ministry of Science and Technology (National key research and development program) [2017YFA0506200]
- Natural Science Foundation of Jiangsu Province [BK20170006, BK20160379]
- Chinese National Thousand Talents Program
- CAMS Initiative for Innovative Medicine (CAMS-I2M) [2016-I2M-1-005]
- ERC [677251]
- European Research Council (ERC) [677251] Funding Source: European Research Council (ERC)
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 mu M) 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-y 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.
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