The SPPL3-defined glycosphingolipid repertoire orchestrates HLA class I-mediated immune responses

Jongsma, M.L.M.; Waard, A.A. de; 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.S.; Huppa, J.B.; Wuhrer, M.; Brummelkamp, T.R.; Neefjes, J.; Spaapen, R.M.

doi:doi:10.1016/j.immuni.2020.11.003

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...Show moreHLA 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.
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The SPPL3-defined glycosphingolipid repertoire orchestrates HLA class I-mediated immune responses