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

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 target...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Vol. 54; no. 1; p. 132
Main Authors: Jongsma, Marlieke L M, de Waard, Antonius A, Raaben, Matthijs, Zhang, Tao, Cabukusta, Birol, Platzer, René, Blomen, Vincent A, Xagara, Anastasia, Verkerk, Tamara, Bliss, Sophie, Kong, Xiangrui, Gerke, Carolin, Janssen, Lennert, Stickel, Elmer, Holst, Stephanie, Plomp, Rosina, Mulder, Arend, Ferrone, Soldano, Claas, Frans H J, Heemskerk, Mirjam H M, Griffioen, Marieke, Halenius, Anne, Overkleeft, Hermen, Huppa, Johannes B, Wuhrer, Manfred, Brummelkamp, Thijn R, Neefjes, Jacques, Spaapen, Robbert M
Format: Journal Article
Language:English
Published: United States 12.01.2021
Subjects:
Antigen Presentation
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glioma - immunology
Glioma - mortality
Glycosphingolipids - immunology
Glycosphingolipids - metabolism
Glycosyltransferases - metabolism
Histocompatibility Antigens Class I - immunology
Histocompatibility Antigens Class I - metabolism
HLA Antigens - immunology
HLA Antigens - metabolism
Humans
Immunotherapy - methods
Lymphocyte Activation
Signal Transduction
Survival Analysis
Tumor Escape
antigen presentation
immune recognition
B3GNT5
glycosphingolipids
immunotherapy
HLA class I
MHC class I
glioma
T cells
SPPL3
ISSN:1097-4180, 1097-4180
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Summary: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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ISSN:1097-4180
1097-4180
DOI:10.1016/j.immuni.2020.11.003