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

J Wang, J Sun, LN Liu, DB Flies, X Nie, M Toki… - Nature medicine, 2019 - nature.com
J Wang, J Sun, LN Liu, DB Flies, X Nie, M Toki, J Zhang, C Song, M Zarr, X Zhou, X Han
Nature medicine, 2019nature.com
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 …
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.
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