Jäger, D. (Dirk)

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    Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma
    (2022) Banales, J.M. (Jesús M.); Stenzinger, A. (Albrecht); Köhler, B.C. (Bruno C.); Westphalen, C.B. (Christoph B.); Albrecht, T. (Thomas); Xu, K. (Kaiyu); Illert, A.L. (Anna L.); Kelmendi, E. (Eblina); Kessler, A. (Annika); Spiekermann, K. (Karsten); Ochsenreiter, S. (Sebastian); Hübschmann, D. (Daniel); Fröhling, S. (Stefan); Springfeld, C. (Christoph); Roessler, S. (Stephanie); Hoffmeister-Wittmann, P. (Paula); Nader, L. (Luisa); Siveke, J. (Jens); Jäger, D. (Dirk); Fritzsche, S. (Sarah); Goeppert, B. (Benjamin); Brors, B. (Benedikt); Boeck, S. (Stefan); Boerries, M. (Melanie); Uhrig, S. (Sebastian); Schmitt, N. (Nathalie); Günther, M. (Michael); Bauer, S. (Sebastian); Korell, F. (Felix); Schulze-Osthoff, K. (Klaus); Kreutzfeld, S. (Simon); Horak, P. (Peter); Scherr, A.L. (Anna Lena); Sobol, B. (Benjamin); Trojan, J. (Jörg); Weichert, W. (Wilko); Hüllein, J. (Jennifer); Weiler, S. (Sofia); Glimm, H. (Hanno); Nichetti, F. (Federico); Bitzer, M. (Michael); Schirmacher, P. (Peter); Mock, A. (Andreas); Kindler, T. (Thomas); Heilig, C.E. (Christoph E.); Ormanns, S. (Steffen); Folprecht, G. (Gunnar); Klauschen, F. (Frederick)
    Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.
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    Classification of current anticancer immunotherapies
    (Impact Journals, 2014) Bracci, L. (Laura); Silva-Santos, B. (Bruno); Mach, J.P. (Jean-Pierre); Hoos, A. (Axel); Abastado, J.P. (Jean-Pierre); Ayyoub, M. (Maha); Whiteside, T.L. (Theresa L.); Vile, R.G. (Richard G.); Rizvi, N. (Naiyer); Galon, J. (Jerome); Odunsi, A. (Adekunke); Kirkwood, J.M. (John M.); Galluzzi, L. (Lorenzo); Ghiringhelli, F. (François); Cerundolo, V. (Vincenzo); Gabrilovich, D.I. (Dmitry I.); Melief, C.J. (Cornelis J.); Speiser, D.E. (Daniel E.); Castoldi, F. (Francesca); Kalinski, P. (Pawel); Senovilla, L. (Laura); Tartour, E. (Eric); Colombo, M.P. (Mario P.); Schreiber, H. (Hans); Jäger, D. (Dirk); Mavilio, D. (Domenico); Kroemer, G. (Guido); Apte, R.N. (Ron N.); Porgador A. (Ángel); Blay, J.Y. (Jean-Yves); Fucíková, J. (Jitka); Rabinovich, G.A. (Gabriel A.); Sautès-Fridman, C. (Catherine); Lugli, E. (Enrico); Fridman, W.H. (Wolf H.); Baracco, E.E. (Elisa Elena); Van-Der-Burg, S.H. (Sjoerd H.); Klein, E. (Eva); Srivastava, P.K. (Pramod K.); Kärre, K. (Klas); Gnjatic,S. (Sacha); Agostinis, P. (Patrizia); Aranda, F. (Fernando); Lewis, C.E. (Claire E.); Bloy, N. (Norma); Vacchelli, E. (Erika); Caignard, A. (Anne); Melero, I. (Ignacio); Kiessling, R. (Rolf); Restifo, N.P. (Nicholas P.); Smyth, M.J. (Mark J.); Zitvogel, L. (Laurence); Fearon, D.T. (Douglas T.); Seliger, B. (Barbara); Prendergast, G.C. (George C.); Pienta, K.J. (Kenneth J.); Wolchok, J.D. (Jedd D.); Clayton, A. (Aled); Cavallo, F. (Federica); Hosmalin, A. (Anne); Knuth, A. (Alexander); Lotze, M.T. (Michael T.); Coussens, L. (Lisa); Beckhove, P. (Philipp); Gilboa, E. (Eli); Mittendorf, E.A. (Elizabeth A.); Palucka, A.K. (Anna Karolina); Weber, J.S. (Jeffrey S.); Talmadge, J.E. (James E.); Celis, E. (Esteban); Castelli, C. (Chiara); Spisek, R. (Radek); Zou, W. (Weiping); Eggermont, A.M. (Alexander M.); Garg, A. (Abhishek); Okada, H. (Hideho); Buque, A. (Aitziber); Mattei, F. (Fabrizio); Bravo-San-Pedro, J.M. (José-Manuel); Moretta, L. (Lorenzo); Dhodapkar, M.V. (Madhav V.); Van-Den-Eynde, B.J. (Benoît J.); Peter, M.E. (Marcus E.); Shiku, H. (Hiroshi); Liblau, R. (Roland); Giaccone, G. (Giuseppe); Kepp, O. (Oliver); Wagner, H. (Hermann)
    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.