Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells
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Author
Stanczak, Michal A
Siddiqui, Shoib S
Trefny, Marcel P
Thommen, Daniela S
Boligan, Kayluz Frias
von Gunten, Stephan
Tzankov, Alexandar
Tietze, Lothar
Lardinois, Didier
Heinzelmann-Schwarz, Viola
von Bergwelt-Baildon, Michael
Zhang, Wu
Lenz, Heinz-Josef
Han, Younghun
Amos, Christopher I
Syedbasha, Mohammedyaseen
Egli, Adrian
Stenner, Frank
Speiser, Daniel E
Varki, Ajit
Zippelius, Alfred
Läubli, Heinz
Attention
2299/24017
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.
Publication date
2018-11-01Published in
Journal of Clinical InvestigationPublished version
https://doi.org/10.1172/JCI120612Other links
http://hdl.handle.net/2299/24017Metadata
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