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  • The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.

The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.

Immunity (2020-12-04)
Marlieke L M Jongsma, Antonius A de Waard, Matthijs Raaben, Tao Zhang, Birol Cabukusta, René Platzer, Vincent A Blomen, Anastasia Xagara, Tamara Verkerk, Sophie Bliss, Xiangrui Kong, Carolin Gerke, Lennert Janssen, Elmer Stickel, Stephanie Holst, Rosina Plomp, Arend Mulder, Soldano Ferrone, Frans H J Claas, Mirjam H M Heemskerk, Marieke Griffioen, Anne Halenius, Hermen Overkleeft, Johannes B Huppa, Manfred Wuhrer, Thijn R Brummelkamp, Jacques Neefjes, Robbert M Spaapen
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.

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