Engagement of sialylated glycans with Siglec receptors on myeloid suppressor cells inhibit anti-cancer immunity via CCL2

Overexpression of sialic acids on glycans, called hypersialylation is a common alteration found in cancer. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on myeloid-derived suppressor cells (MDSCs) and their interaction with Siglec receptors. We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to strong reduction of their suppressive potential. We further identified CCL2 as mediator involved in T cell suppression upon interaction of sialoglycans and Siglec receptors on MDSCs. Our results provide mechanistic insights how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression. ![Figure][1] ### Competing Interest Statement H.L. received travel grants and consultant fees from Bristol-Myers Squibb (BMS), Alector, InterVenn, GlycoEra, Merck Sharp & Dohme (MSD). H.L. received research support from BMS, Novartis, GlycoEra and PalleonPharmaceuticals. H.L. and N.M.R. are cofounders of Singenavir Ltd. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. * A549-sia : A549 cells stably expressing viral H1N1 sialidase B16F10-sia : B16F10 cells stably expressing viral H1N1 sialidase DCs : Dendritic cells DMEM : Dulbecco’s Modified Eagle Medium E:T : Effector:target gMDSC : Granulocytic myeloid-derived suppressor cell GNE : UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase GzmB : GranzymeB HeLa-sia : HeLa cells stably expressing viral H1N1 sialidase ITIM : Immunoreceptor tyrosine-based inhibitory motifs KO : Knockout MALII : Maackia Amurensis Lectin II MDSC : Myeloid-derived suppressor cell MFI : Mean fluorescence intensity mMDSC : Monocytic myeloid-derived suppressor cell MS : Mass spectrometry NK cells : Natural Killer cells PBMCs : Peripheral blood mononuclear cells PMN-MDSC : Polymorphonuclear myeloid-derived suppressor cell PNA : Peanut Agglutinin RPMI : Roswell Park Memorial Institute Medium Siglec : Sialic acid-binding immunoglobulin-like lectin SigEΔLysM : Siglec-ExLysM-Cre; mice with knockout of Siglec-E on LysM expressing cells SigEWT : Siglec-E wildtype SNA : Sambucus Nigra Lectin TAM : Tumor-associated macrophages TME : Tumor microenvironment V.c. : Vibrio cholerae [1]: pending:yes