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.
Jun Wang  #  1 ,  Jingwei Sun  #  1 ,  Linda N Liu  2 ,  Dallas B Flies  2 ,  Xinxin Nie  1 ,  Maria Toki  3 ,  Jianping Zhang  1 ,  Chang Song  2 ,  Melissa Zarr  2 ,  Xu Zhou  1 ,  Xue Han  1 ,  Kristina A Archer  2 ,  Thomas O'Neill  2 ,  Roy S Herbst  4 ,  Agedi N Boto  1  3 ,  Miguel F Sanmamed  1 ,  Solomon Langermann  2 ,  David L Rimm  3  4 ,  Lieping Chen  5  6
Affiliations
  • 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. [email protected].
  • 6. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • # Contributed equally.
PMID: 30833750 DOI: 10.1038/s41591-019-0374-x
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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