50 Years ESDR Anniversary Lecture 4
Title: A commotion in the skin: Developing melanoma immune therapies
Date: Friday 24 September 2021, 17.00-17.30
The Röcken laboratory explores the capacity of adaptive immunity to prevent or treat inflammatory, infectious or cancer diseases. Focussing on T cell cytokines, they analyze the possibilities to modulate and to generate T cells for immune therapies.
Thus, the lab was the first to show that either interferon producing TH1 cells or interleukin-4 producing TH2 cells always differentiate from undetermined precursors. Subsequently, the lab characterized major signals allowing the antigen-specific induction of either TH1 or TH2 cells in vivo, first in mice and then in humans. This allowed the lab to show, first in mice and then in humans, that it is possible to successfully treat inflammatory autoimmune diseases just by changing the cytokines autoreactive T cells produced in vivo. This was originally established in a model of multiple sclerosis in mice and further developed as “cytokine mediated immune deviation” for psoriasis, the rationale for today’s anti-IL-17 or anti-IL-23 based immune therapies.
More recently, the laboratory explores the role of the adaptive immune system and of T cell cytokines for cancer therapies. The Röcken lab is especially interested in understanding the signals by which T cells can either impair or promote cancer development. They demonstrated that T cells cannot only kill cancer cells but that the immune system can efficiently arrest cancer growth by inducing a permanent growth arrest, called senescence, in cancer cells.
Importantly, this also applies to melanoma immune therapies with immune checkpoint inhibitors. The data show that these inhibitors control only those cancers where interferon-dominated immune responses can still arrest the cell cycle. In consequence, efficient cancer immune control requires the cytokine-induced cell cycle arrest to control those cancer cells that escape from the established cytotoxic mechanisms.
Röcken M, Urban JF, Shevach EM. Infection breaks T-cell tolerance. Nature 359:79-82 (1992).
Röcken M, Urban J, Shevach EM. Antigen-specific activation, tolerization, and reactivation of the interleukin 4 pathway in vivo. J Exp Med 179:1885-1893 (1994).
Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, Shevach EM, Röcken M. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 180:1961-1966 (1994).
Biedermann T, Zimmermann S, Himmelrich H, Gumy A, Egeter O, Sakrauski AK, Seegmüller I, Voigt H, Launois P, Levine AD, Wagner H, Heeg K, Louis JA, Röcken M. Interleukin 4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nature Immunol 2:1054-1060 (2001).
Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, van der Zee R, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlondorff D, Plewig G, Sander CA, Röcken M. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nature Med 9:40-46 (2003).
Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, Reusch U, Bubeck A, Louis J, Mailhammer R, Riethmuller G, Koszinowski U, Röcken M. Natural killer cells activated by MHC class Ilow targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19:561-569 (2003).
Müller-Hermelink N, Braumüller H, Pichler B, Kneilling M, Wieder T, Mailhammer R, Schaak K, Ghoreschi K, Yazdi A, Haubner R, Sander CA, Mocikat R, Schwaiger M, Förster I, Huss R, Weber WA, Röcken M. TNFR1- and IFN--signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13:507-518 (2008).
Ghoreschi K, Brück J, Kellerer C, Deng C, Peng H, Rothfuss O, Hussain RZ, Gocke AR, Respa A, Glocova I, Valtcheva N, Alexander E, Feil S, Feil R, Schulze-Osthoff K, Rupec RA, Lovett-Racke AE, Dringen R, Racke MK, Röcken M. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 208:2291-2303 (2011).
Hoetzenecker W, Echtenacher B, Guenvoa E, Hoetzenecker K, Woelbing F, Brueck J, Teske A, Valtcheva N, Fuchs K, Kneilling M, Park JH, Kim KH, Kim KW, Hoffmann P, Krenn C, Hai T, Ghoreschi K, Biedermann T, Röcken M. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nature Med 18:128-134 (2012).
Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Fehrenbacher B, Berdel J, Niessner H, Meier F, van den Broek M, Häring HU, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Röcken M. T-helper-1-cell cytokines drive cancer into senescence. Nature 494:361-365 (2013).
Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim KW, Park JH, Seo JH, Ignatova D, Cozzio A, Levesque MP, Volz T, Köberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schäkel K, Amarov B, Eichner M, Schaller M, Clark RA, Röcken M, Biedermann T. IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci USA 112:2163-2168 (2015).
Brenner E, Schörg BF, Ahmetlic F, Wieder T, Hilke FJ, Simon N, Schroeder C, Demidov G, Riedel T, Fehrenbacher B, Schaller M, Forschner A, Eigentler T, Niessner H, Sinnberg T, Böhm KS, Hömberg N, Braumüller H, Dauch D, Zwirner S, Zender L, Sonanini D, Geishauser A, Bauer J, Eichner M, Jarick K, Beilhack A, Biskup S, Döcker D, Schadendorf D, Quintanilla-Martinez L, Pichler B, Kneilling M, Mocikat R, Röcken M. Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours. Nat Commun (in press).