2. Academic Validation
  3. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy

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

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. lieping.chen@yale.edu.
  • 6 Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. lieping.chen@yale.edu.
  • # 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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