Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

J Clin Invest. 2018 Nov 1;128(11):4912-4923. doi: 10.1172/JCI120612. Epub 2018 Sep 24.


First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.

Keywords: Cancer immunotherapy; Immunology; Oncology; T cells.

Publication types

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

MeSH terms

  • Antigens, CD* / genetics
  • Antigens, CD* / immunology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / immunology*
  • Humans
  • Male
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / immunology
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / mortality
  • Neoplasms* / pathology
  • Polymorphism, Genetic*
  • Sialic Acid Binding Immunoglobulin-like Lectins* / genetics
  • Sialic Acid Binding Immunoglobulin-like Lectins* / immunology
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / pathology


  • Antigens, CD
  • Neoplasm Proteins
  • SIGLEC9 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins