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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Vydáno v:	Immunity (Cambridge, Mass.) Ročník 54; číslo 1; s. 132
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 12.01.2021
Témata:	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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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2020.11.003