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
  • 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.
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