2. Academic Validation
  3. 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. 2021 Jan 12;54(1):132-150.e9. doi: 10.1016/j.immuni.2020.11.003.
Marlieke L M Jongsma 1,  Antonius A de Waard 2,  Matthijs Raaben 3,  Tao Zhang 4,  Birol Cabukusta 5,  René Platzer 6,  Vincent A Blomen 3,  Anastasia Xagara 2,  Tamara Verkerk 2,  Sophie Bliss 2,  Xiangrui Kong 2,  Carolin Gerke 7,  Lennert Janssen 5,  Elmer Stickel 3,  Stephanie Holst 4,  Rosina Plomp 4,  Arend Mulder 8,  Soldano Ferrone 9,  Frans H J Claas 8,  Mirjam H M Heemskerk 10,  Marieke Griffioen 10,  Anne Halenius 11,  Hermen Overkleeft 12,  Johannes B Huppa 6,  Manfred Wuhrer 4,  Thijn R Brummelkamp 13,  Jacques Neefjes 5,  Robbert M Spaapen 14
Affiliations

Affiliations

  • 1 Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands; Oncode Institute and Department of Cell and Chemical Biology, LUMC, Leiden, the Netherlands.
  • 2 Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands.
  • 3 Oncode Institute, Division of Biochemistry, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 4 Center for Proteomics and Metabolics, LUMC, Leiden, the Netherlands.
  • 5 Oncode Institute and Department of Cell and Chemical Biology, LUMC, Leiden, the Netherlands.
  • 6 Institut für Hygiene und Angewandte Immunologie, Vienna, Austria.
  • 7 Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 8 Department of Immunology, LUMC, Leiden, the Netherlands.
  • 9 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
  • 11 Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 12 Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • 13 Oncode Institute, Division of Biochemistry, the Netherlands Cancer Institute, Amsterdam, the Netherlands; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Cancer Genomics Center, Amsterdam, the Netherlands.
  • 14 Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 33271119 DOI: 10.1016/j.immuni.2020.11.003
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.

Keywords

B3GNT5; HLA class I; MHC class I; SPPL3; T cells; antigen presentation; glioma; glycosphingolipids; immune recognition; immunotherapy.

Figures
Products