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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Proteome / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • T-Lymphocytes / immunology


  • Epitopes
  • Immunoglobulins
  • Membrane Proteins
  • Proteome
  • RNA, Messenger
  • SIGLEC15 protein, human
  • Siglec-15 protein, mouse