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.
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
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