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

Michal A Stanczak, Shoib S Siddiqui, Marcel P Trefny, Daniela S Thommen, Kayluz Frias Boligan, Stephan von Gunten, Alexandar Tzankov, Lothar Tietze, Didier Lardinois, Viola Heinzelmann-Schwarz, Michael von Bergwelt-Baildon, Wu Zhang, Heinz-Josef Lenz, Younghun Han, Christopher I Amos, Mohammedyaseen Syedbasha, Adrian Egli, Frank Stenner, Daniel E Speiser, Ajit VarkiAlfred Zippelius, Heinz Läubli

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)4912-4923
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number11
Early online date21 Aug 2018
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

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

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