Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
Uta M. Demel, Marlitt Böger, Schayan Yousefian, Corinna Grunert, Le Zhang, Paul W. Hotz, Adrian Gottschlich, Hazal Köse, Konstandina Isaakidis, Dominik Vonficht, Florian Grünschläger, Elena Rohleder, Kristina Wagner, Judith Dönig, Veronika Igl, Bernadette Brzezicha, Francis Baumgartner, Stefan Habringer, Jens Löber, Björn Chapuy, Carl Weidinger, Sebastian Kobold, Simon Haas, Antonia B. Busse, Stefan Müller, Matthias Wirth, Markus Schick, Ulrich Keller
Uta M. Demel, Marlitt Böger, Schayan Yousefian, Corinna Grunert, Le Zhang, Paul W. Hotz, Adrian Gottschlich, Hazal Köse, Konstandina Isaakidis, Dominik Vonficht, Florian Grünschläger, Elena Rohleder, Kristina Wagner, Judith Dönig, Veronika Igl, Bernadette Brzezicha, Francis Baumgartner, Stefan Habringer, Jens Löber, Björn Chapuy, Carl Weidinger, Sebastian Kobold, Simon Haas, Antonia B. Busse, Stefan Müller, Matthias Wirth, Markus Schick, Ulrich Keller
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Research Article Immunology Oncology

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

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.

Authors

Uta M. Demel, Marlitt Böger, Schayan Yousefian, Corinna Grunert, Le Zhang, Paul W. Hotz, Adrian Gottschlich, Hazal Köse, Konstandina Isaakidis, Dominik Vonficht, Florian Grünschläger, Elena Rohleder, Kristina Wagner, Judith Dönig, Veronika Igl, Bernadette Brzezicha, Francis Baumgartner, Stefan Habringer, Jens Löber, Björn Chapuy, Carl Weidinger, Sebastian Kobold, Simon Haas, Antonia B. Busse, Stefan Müller, Matthias Wirth, Markus Schick, Ulrich Keller

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Figure 5

Activated SUMOylation restricts cytokine-dependent induction of MHC-I.

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Activated SUMOylation restricts cytokine-dependent induction of MHC-I. (...
(A) MHC-I expression on SU-DHL-4 cells treated either with control, SUMOi (100 nM, 72 h), or SUMOi (100 nM, 72 h) and IFN-γ (100 U/mL) for 24 hours (n = 3). Data represent the mean ± SD. P values were determined by ANOVA with Tukey’s post hoc test. (B) MHC-I expression of OCI-Ly1 cells treated with control, SUMOi (40 nM, 72 h), or SUMOi (40 nM, 72 h) and IFN-γ (100 U/mL) for 24 hours (n = 3). Data represent the mean ± SD. P values were determined by ANOVA with Tukey’s post hoc test. (C) Immunoblot analysis of SU-DHL-4 cells treated with IFN-γ (100 U/mL) for the indicated durations after pretreatment with SUMOi (100 nM) or control for 72 hours. (D) STAT1 mRNA expression analysis of SU-DHL-4 (100 nM, 72 h; n = 3) and OCI-Ly1 (40 nM, 72 h; n = 4) cells treated with control or SUMOi and IFN-γ (100 U/mL) for 1 hour, as indicated. Data represent the mean ± SD. P values were determined by ANOVA with Tukey’s post hoc test. (E) Immunoblot analysis of P493-6 cells treated with 60 nM SUMOi for 48 hours. (F) Activity of the antigen processing and presentation core machinery determined with ssGSEA in cell lines listed in the Cancer Cell Line Encyclopedia. Each dot represents an individual cancer cell line (NES). Horizontal black lines indicate the median. (G) MHC-I expression after incubation with IFN-γ (100 U/mL) for 24 hours in the indicated cell lines pretreated with either SUMOi (U-2-OS, Kelly, MCF-7: 100 nM; H1299: 500 nM) or control for 72 hours. (H) Immunoblot analysis of U-2-OS cells after transfection with specific SUMO1, SUMO2, or control siRNAs (72 h) and treatment or not with IFN-γ (100 U/mL) for 24 hours.