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Nat Med. 2019 Apr;25(4):656-666. doi: 10.1038/s41591-019-0374-x. Epub 2019 Mar 4.

Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
2
NextCure Inc, Beltsville, MD, USA.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
4
Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. lieping.chen@yale.edu.
6
Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. lieping.chen@yale.edu.

Abstract

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.

PMID:
30833750
DOI:
10.1038/s41591-019-0374-x
[Indexed for MEDLINE]

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