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

Stanczak, Michal AMichal AStanczakSiddiqui, Shoib SShoib SSiddiquiTrefny, Marcel PMarcel PTrefnyThommen, Daniela SDaniela SThommenFrias Boligan, KayluzKayluzFrias Boliganvon Gunten, StephanStephanvon GuntenTzankov, AlexandarAlexandarTzankovTietze, LotharLotharTietzeLardinois, DidierDidierLardinoisHeinzelmann-Schwarz, ViolaViolaHeinzelmann-Schwarzvon Bergwelt-Baildon, Michael SMichael Svon Bergwelt-BaildonZhang, WuWuZhangLenz, Heinz-JosefHeinz-JosefLenzHan, YounghanYounghanHanAmos, Christopher IChristopher IAmosSyedbasha, MohammedyaseenMohammedyaseenSyedbashaEgli, AdrianAdrianEgliStenner, FrankFrankStennerSpeiser, Daniel EDaniel ESpeiserVarki, AjitAjitVarkiZippelius, AlfredAlfredZippeliusLäubli, HeinzHeinzLäubli2024-10-252024-10-252018-11-01https://boris-portal.unibe.ch/handle/20.500.12422/164183First 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.enCancer immunotherapy Immunology Oncology T cells600 - Technology::610 - Medicine & healthSelf-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells.article10.7892/boris.1197983013025510.1172/JCI120612