Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.
Aged
Animals
Antibodies, Monoclonal, Humanized
/ therapeutic use
Antineoplastic Agents, Immunological
/ therapeutic use
CD8-Positive T-Lymphocytes
/ pathology
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Male
Melanoma
/ drug therapy
Melanoma, Experimental
/ drug therapy
Mice, Inbred BALB C
Middle Aged
Molecular Targeted Therapy
Nivolumab
/ therapeutic use
Phosphotransferases (Alcohol Group Acceptor)
/ genetics
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Skin Neoplasms
/ drug therapy
Survival Rate
T-Lymphocytes, Regulatory
/ pathology
Tumor Escape
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 01 2020
23 01 2020
Historique:
received:
10
04
2018
accepted:
18
12
2019
entrez:
25
1
2020
pubmed:
25
1
2020
medline:
25
4
2020
Statut:
epublish
Résumé
Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
Identifiants
pubmed: 31974367
doi: 10.1038/s41467-019-14218-7
pii: 10.1038/s41467-019-14218-7
pmc: PMC6978345
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents, Immunological
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Nivolumab
31YO63LBSN
pembrolizumab
DPT0O3T46P
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
Sphk1 protein, mouse
EC 2.7.1.-
sphingosine kinase
EC 2.7.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
437Références
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