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

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. Blockade of sialic acid-binding protein Siglec-15 expressed in cancer and tumor-infiltrating myeloid cells reverses immunesupression and represents a novel target for cancer immunotherapy independent from the PD-1/PD-L1 axis.
Author(s): Jun Wang [sup.1] , Jingwei Sun [sup.1] , Linda N. Liu [sup.2] , Dallas B. Flies [sup.2] , Xinxin Nie [sup.1] , Maria Toki [sup.3] , Jianping Zhang [sup.1] [...]