2. Academic Validation
  3. Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer

Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer

  • J Clin Invest. 2022 May 2;132(9):e152383. doi: 10.1172/JCI152383.
Uta M Demel 1 2 3,  Marlitt Böger 1 2,  Schayan Yousefian 1 4 5,  Corinna Grunert 1 2,  Le Zhang 1 2,  Paul W Hotz 6,  Adrian Gottschlich 7,  Hazal Köse 1 2,  Konstandina Isaakidis 1 2,  Dominik Vonficht 8 9 10,  Florian Grünschläger 8 9 10,  Elena Rohleder 1 2,  Kristina Wagner 6,  Judith Dönig 6,  Veronika Igl 7,  Bernadette Brzezicha 11,  Francis Baumgartner 1 2 3,  Stefan Habringer 1 2 3,  Jens Löber 12,  Björn Chapuy 1 4 12,  Carl Weidinger 13,  Sebastian Kobold 7 14 15 16,  Simon Haas 1 4 5 8 9 10,  Antonia B Busse 1 2,  Stefan Müller 6,  Matthias Wirth 1 2 14,  Markus Schick 1 2,  Ulrich Keller 1 2 14
Affiliations

Affiliations

  • 1 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 2 Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
  • 3 Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin, Germany.
  • 4 BIH at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 5 Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • 6 Institute of Biochemistry II, Goethe University Frankfurt, Medical School, Frankfurt, Germany.
  • 7 Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany.
  • 8 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
  • 9 Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
  • 10 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 11 Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO), Berlin, Germany.
  • 12 Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany.
  • 13 Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 14 German Center for Translational Cancer Research (DKTK), DKFZ, Heidelberg, Germany.
  • 15 DKTK, Partner Site Munich, Munich, Germany.
  • 16 Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.
PMID: 35499080 DOI: 10.1172/JCI152383
Abstract

Activated SUMOylation is a hallmark of Cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed Cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to Cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of Cancer immunotherapies.

Keywords

Antigen presentation; Immunology; Immunotherapy; Oncology; Ubiquitin-proteosome system.

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