The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-mediated immune responses

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Item Type:	Article
Title:	The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-mediated immune responses
Creators Name:	Jongsma, M.L.M., de Waard, A.A., Raaben, M., Zhang, T., Cabukusta, B., Platzer, R., Blomen, V.A., Xagara, A., Verkerk, T., Bliss, S., Kong, X., Gerke, C., Janssen, L., Stickel, E., Holst, S., Plomp, R., Mulder, A., Ferrone, S., Claas, F.H.J., Heemskerk, M.H.M, Griffioen, M., Halenius, A., Overkleeft, H., Huppa, J.B., Wuhrer, M., Brummelkamp, T.R., Neefjes, J. and Spaapen, R.M.
Abstract:	HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8(+) T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8(+) T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity.
Keywords:	HLA Class I, MHC Class I, Glycosphingolipids, B3GNT5, SPPL3, T Cells, Antigen Presentation, Immunotherapy, Immune Recognition, Glioma
Source:	Immunity
ISSN:	1074-7613
Publisher:	Cell Press / Elsevier
Volume:	54
Number:	1
Page Range:	132-150.e9
Date:	12 January 2021
Additional Information:	Erratum in: Immunity 54(2):387
Official Publication:	https://doi.org/10.1016/j.immuni.2020.11.003
PubMed:	View item in PubMed

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