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Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
(2022)
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 Thomas Maximilian ; Kobold, Sebastian ; Haas, Simon ; Busse, Antonia B. ; Müller, Stefan ; Wirth, Matthias ; Schick, Markus ; Keller, Ulrich
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.
A highly efficient method for chromosomal integration of cloned DNA into Methanosarcina spp. was developed utilizing the site-specific recombination system from the Streptomyces phage PhiC31. Host strains expressing the PhiC31 integrase gene and carrying an appropriate recombination site can be transformed with non-replicating plasmids carrying the complementary recombination site at efficiencies similar to those obtained with self-replicating vectors. We have also constructed a series of hybrid promoters that combine the highly expressed M. barkeri PmcrB promoter with binding sites for the tetracycline-responsive, bacterial TetR protein. These promoters are tightly regulated by the presence or absence of tetracycline in strains that express the tetRgene. The hybrid promoters can be used in genetic experiments to test gene essentiality by placing a gene of interest under their control. Thus, growth of strains with tetR-regulated essential genes becomes tetracycline-dependent. A series of plasmid vectors that utilize the site-specific recombination system for construction of reporter gene fusions and for tetracycline regulated expression of cloned genes are reported. These vectors were used to test the efficiency of translation at a variety of start codons. Fusions using an ATG start site were the most active, whereas those using GTG and TTG were approximately one half or one fourth as active, respectively. The CTG fusion was 95% less active than the ATG fusion.
Albinger, Nawid ; Pfeifer, Rita ; Nitsche, Marcus ; Mertlitz, Sarah ; Campe, Julia ; Stein, Katja ; Kreyenberg, Hermann ; Schubert, Ralf ; Quadflieg, Melissa ; Schneider, Dina ; Kühn, Michael W. M. ; Penack, Olaf ; Zhang, Congcong ; Möker, Nina ; Ullrich, Evelyn
Acute myeloid leukemia (AML) is a malignant disorder derived from neoplastic myeloid progenitor cells characterized by abnormal proliferation and differentiation. Although novel therapeutics have recently been introduced, AML remains a therapeutic challenge with insufficient cure rates. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies including acute lymphoblastic leukemia (ALL). However, the application of CAR-T cells appears to be challenging due to the enormous molecular heterogeneity of the disease and potential long-term suppression of hematopoiesis. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects.
Thomas, Christoph ; Aller, Stephen G. ; Beis, Konstantinos ; Carpenter, Elisabeth P. ; Chang, Geoffrey ; Chen, Lei ; Dassa, Elie ; Dean, Michael ; Duong Van Hoa, Franck ; Ekiert, Damian ; Ford, Robert ; Gaudet, Rachelle ; Gong, Xin ; Holland, I. Barry ; Huang, Yihua ; Kahne, Daniel K. ; Kato, Hiroaki ; Koronakis, Vassilis ; Koth, Christopher M. ; Lee, Youngsook ; Lewinson, Oded ; Lill, Roland ; Martinoia, Enrico ; Murakami, Satoshi ; Pinkett, Heather W. ; Poolman, Bert ; Rosenbaum, Daniel ; Sarkadi, Balazs ; Schmitt, Lutz ; Schneider, Erwin ; Shi, Yigong ; Shyng, Show‐Ling ; Slotboom, Dirk Jan ; Tajkhorshid, Emad ; Tieleman, Dirk Peter ; Ueda, Kazumitsu ; Váradi, András ; Wen, Po‐Chao ; Yan, Nieng ; Zhang, Peng ; Zheng, Hongjin ; Zimmer, Jochen ; Tampé, Robert
Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs: