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 8

SUMOi globally alters the immune landscape.

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SUMOi globally alters the immune landscape. (A) UMAP visualization of sp...
(A) UMAP visualization of spleen scRNA-Seq data from control and SUMOi-treated mice. (B) UMAP visualization of spleen scRNA-Seq data from control mice (n = 3). (C) UMAP visualization of spleen scRNA-Seq data from SUMOi-treated mice (n = 3). (D) Detection of differentially abundant cell populations in the spleens of control and SUMOi-treated mice using DA-Seq (71). Cells are colored by the DA-Seq measure. Yellow indicates greater abundance after SUMOi treatment; dark blue indicates greater abundance in the control. (E) The T cell populations identified in A were separated and reclustered. The UMAP visualization shows T cells for both conditions. (F) Detection of differentially abundant T cell populations in control and SUMOi-treated mice with DA-Seq. Cells are colored by the DA-Seq measure. Yellow indicates greater abundance after SUMOi treatment; dark blue indicates greater abundance in control mice. (G and H) Differential abundance testing on mouse-wise pseudo-bulks (white dots, n = 3). Bar plots indicate the respective subpopulation frequencies stratified by condition. The center line of the box plot is the median. The box extends from the 25th to 75th percentiles. The whisker length is from minimum to maximum. Significance was determined using a negative binomial generalized linear model. (G) Significantly more abundant cell populations were detected in control mice. (H) Significantly more abundant cell populations were detected in SUMOi-treated mice. (I–K) Differential expression analysis in B cells (I), naive CD4+ T cells (J), and naive CD8+ T cells (K) of the genes of interest (normalized expression) and IFN response scores (arbitrary expression). Gray dots represent individual cells. White dots indicate the median per mouse-wise pseudo-bulk. The back line indicates the median across all cells. Wilcoxon’s rank-sum test was applied to determine significance. The adjusted P values (Bonferroni’s correction) are shown. The pie charts indicate the number of cells with normalized counts equal to 0 (gray) and normalized counts greater than 0 (black) for the respective genes and condition.