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

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

doi:10.1172/jci152383

Cited by 37 publications

(24 citation statements)

References 70 publications

(105 reference statements)

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“…Integration of antibodies or small-molecule inhibitors to prevent metabolite-driven immunosuppression, or blockade of checkpoint and immunosuppressive mechanisms (Fig. 4b , e ), for instance, might lead to a multifaceted outcome: boosting CAR NK cell function, hindering signals from suppressive cells in the TME and supporting the function of other immune effector cells 197 – 199 . Lastly, engineering NK cells to become resistant to CD38-mediated fratricide will enable NK cell-based treatment approaches to be combined with anti-CD38 monoclonal antibodies and allow NK cell immunotherapy to move into earlier lines of treatment in the setting of multiple myeloma 50 (Fig.…”

Section: Clinical Lessons Learnedmentioning

confidence: 99%

Natural killer cells in antitumour adoptive cell immunotherapy

2022

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Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.

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Section: Clinical Lessons Learnedmentioning

confidence: 99%

Natural killer cells in antitumour adoptive cell immunotherapy

2022

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“…In order to decipher the effects of short term highly specific small-molecule SUMOi on B-cell subsets in more detail, we next opted for Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) analysis (dataset GSE193359). 20 CITE-seq combines the measurements of surface protein levels and transcriptome analysis to determine cellular states and their alterations at single-cell level. 37 In this experiment wt mice were challenged with a lower dose of the SUMO inhibitor subasumstat in line with a recent publication reporting enhanced anti-tumor T-cell capacity upon SUMOi.…”

Section: Resultsmentioning

confidence: 99%

“… 45 So far, only enhanced CD8 + T-cell activation and augmented anti-tumor sensitivity by SUMOimediated reactivation of type I interferon signaling have been reported before. 19 , 20 , 36 We here identified a novel function of SUMO inhibition in remodeling the immune cell landscape by enhancing abundance of cellular subsets involved in the innate and specific immune response.…”

Section: Discussionmentioning

confidence: 96%

Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy

et al. 2022

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Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a pre-clinical murine in vivo model of MYCdriven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B-cells as well as cytotoxic and memory T-cells, subsets that are attributed a key role within a coordinated antitumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of B-cell lymphomas causing massive remodeling of the normal B-cell and T-cell compartment.

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“…Murine Panc02-EpCAM, 4T1, T110299 and CT26-EpCAM have been previously described [41][42][43]. Murine LL/2 were purchased from the European Collection of Authenticated Cell Cultures (ECACC).…”

Section: Cell Linesmentioning

confidence: 99%

Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function

et al. 2022

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Background Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response. Methods Here, we present the impact of the selective adenosine A2A and A2B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma. Results We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo. Conclusions Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.

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

Cited by 37 publications

References 70 publications

Natural killer cells in antitumour adoptive cell immunotherapy

Natural killer cells in antitumour adoptive cell immunotherapy

Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy

Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function

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