| Literature DB >> 33271119 |
Marlieke L M Jongsma1, Antonius A de Waard2, Matthijs Raaben3, Tao Zhang4, Birol Cabukusta5, René Platzer6, Vincent A Blomen3, Anastasia Xagara2, Tamara Verkerk2, Sophie Bliss2, Xiangrui Kong2, Carolin Gerke7, Lennert Janssen5, Elmer Stickel3, Stephanie Holst4, Rosina Plomp4, Arend Mulder8, Soldano Ferrone9, Frans H J Claas8, Mirjam H M Heemskerk10, Marieke Griffioen10, Anne Halenius11, Hermen Overkleeft12, Johannes B Huppa6, Manfred Wuhrer4, Thijn R Brummelkamp13, Jacques Neefjes5, Robbert M Spaapen14.
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.Entities:
Keywords: B3GNT5; HLA class I; MHC class I; SPPL3; T cells; antigen presentation; glioma; glycosphingolipids; immune recognition; immunotherapy
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Year: 2020 PMID： 33271119 PMCID： PMC8722104 DOI： 10.1016/j.immuni.2020.11.003
Source DB: PubMed Journal: Immunity ISSN： 1074-7613 Impact factor: 31.745