Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy.
Animals
Cell Line, Tumor
Cell Proliferation
Epitopes
Humans
Immunoglobulins
/ metabolism
Immunotherapy
Macrophages
/ metabolism
Membrane Proteins
/ metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Myeloid Cells
/ metabolism
Neoplasms
/ immunology
Proteome
/ metabolism
RNA, Messenger
/ genetics
T-Lymphocytes
/ immunology
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
22
03
2018
accepted:
24
01
2019
pubmed:
6
3
2019
medline:
11
5
2019
entrez:
6
3
2019
Statut:
ppublish
Résumé
Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy.
Identifiants
pubmed: 30833750
doi: 10.1038/s41591-019-0374-x
pii: 10.1038/s41591-019-0374-x
pmc: PMC7175920
mid: NIHMS1519622
doi:
Substances chimiques
Epitopes
0
Immunoglobulins
0
Membrane Proteins
0
Proteome
0
RNA, Messenger
0
SIGLEC15 protein, human
0
Siglec-15 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
656-666Subventions
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA196530
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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