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

Autores: Wang, J.; Sun, J.; Liu, L. N.; Flies, D. B.; Nie, X.; Toki, M.; Zhang, J.; Song, C.; Zarr, M.; Zhou, X.; Han, X.; Archer, K. A.; O'Neill, T.; Herbst, R. S.; Boto, A. N.; Fernández de Sanmamed Gutiérrez, Miguel; Langermann, S.; Rimm, D. L.; Chen, L.
Título de la revista: *NATURE MEDICINE* (IF: 36.130)
ISSN: 1546-170X
Volumen: 25
Número: 4
Páginas: 656 - 666
Fecha de publicación: 2019
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-gamma. 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.