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

Stanczak, Michal A; Siddiqui, Shoib S; Trefny, Marcel P; Thommen, Daniela S; Frias Boligan, Kayluz; von Gunten, Stephan; Tzankov, Alexandar; Tietze, Lothar; Lardinois, Didier; Heinzelmann-Schwarz, Viola; von Bergwelt-Baildon, Michael S; Zhang, Wu; Lenz, Heinz-Josef; Han, Younghan; Amos, Christopher I; Syedbasha, Mohammedyaseen; Egli, Adrian; Stenner, Frank; Speiser, Daniel E; Varki, Ajit; ... (2018). Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. Journal of clinical investigation, 128(11), pp. 4912-4923. American Society for Clinical Investigation 10.1172/JCI120612

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First generation immune checkpoint inhibitors including anti-CTLA-4 and 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 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 yet 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 (NSCLC), colorectal and ovarian cancer patients. Siglec-9 expressing T cells co-expressed several inhibitory receptors including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anti-cancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with a reduced survival, and Siglec-9 polymorphisms showed associations with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as new potential target to improve T cell activation for immunotherapy.

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