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

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.

• Authors: 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 Varki, Alfred Zippelius, Heinz Läubli
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 11 Pg. 4912-4923 (11 01 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 30130255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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