The development of effective anti-tumour immunity is capable of restricting tumour development and causing tumour regression. The recent development of antibodies blocking specific checkpoints in T cell activation, such the anti-PD-1 and anti-PD-L1 antibodies, has revolutionized cancer immunotherapy, leading to spectacular success in some patients. However, the effectiveness of the current protocols is restricted to a small subset of patients for reasons that are not understood. Therefore, a better understanding of the mechanisms determining anti-tumour immune responses is required in order to develop better protocols inducing effective anti-tumour immunity in the majority or hopefully all the patients. Death of tumour cells has been shown to induce anti-tumour immunity but it remains unclear whether different types of cell death have different immunogenic properties. Here we propose to study the effect of specific types of tumour cell death on anti-tumour immunity. We will focus particularly on necroptosis, a type of regulated necrotic cell death induced by RIPK3 and its substrate MLKL, which is highly immunogenic due to the massive release of DAMPs. We will compare the effect of tumour cell necroptosis with that of apoptosis in eliciting anti-tumour immunity, in a mouse model of autochthonous melanoma development. We will also study the role of necroptosis and apoptosis when combined with anti-PD-1 blocking antibodies in order to determine the potential synergistic effect of tumour cell death with immunotherapy protocols based on T cell activation checkpoint inhibitors.
Our studies aim to address the potential role of specific types of tumour cell death, namely necroptosis and apoptosis, in triggering anti-tumour immunity, and to explore their potential synergistic effect when combined with T cell activation checkpoint inhibitors. Our results may lead to the development of better immunotherapy protocols combining agents inducing specific types of cancer cell death with checkpoint inhibitors.
Grab, J., Suarez, I., van Gumpel, E., Winter, S., Schreiber, F., Esser, A., Holscher, C., Fritsch, M., Herb, M., Schramm, M., Wachsmuth, L., Pallasch, C., Pasparakis, M., Kashkar, H., and Rybniker, J. (2019). Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat Commun 10, 688.
Krishna-Subramanian, S., Singer, S., Armaka, M., Banales, J.M., Holzer, K., Schirmacher, P., Walczak, H., Kollias, G., Pasparakis, M., and Kondylis, V. (2019). RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury. Cell Death Differ10.1038/s41418-019-0330-9.
Kondylis, V., and Pasparakis, M. (2019). RIP Kinases in Liver Cell Death, Inflammation and Cancer. Trends in Molecular Medicine 25, 47-63.
Liccardi, G., Garcia, L.R., Tenev, T., Annibaldi, A., Legrand, A.J., Robertson, D., Feltham, R., Anderton, H., Darding, M., Peltzer, N., Dannappel, M., Schunke, H., Fava, L.L., Haschka, M.D., Glatter, T., Nesvizhskii, A., Schmidt, A., Harris, P.A., Bertin, J., Gough, P.J., Villunger, A., Silke, J., Pasparakis, M., Bianchi, K., and Meier, P. (2019). RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation. Molecular Cell 73, 413-+.
Polykratis, A., Martens, A., Eren, R.O., Shirasaki, Y., Yamagishi, M., Yamaguchi, Y., Uemura, S., Miura, M., Holzmann, B., Kollias, G., Armaka, M., van Loo, G., and Pasparakis, M. (2019). A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain. Nature Cell Biology 21, 731-42.
Androulidaki A, Wachsmuth L, Polykratis A, and Pasparakis M (2018). Differential role of MyD88 and TRIF signaling in myeloid cells in the pathogenesis of autoimmune diabetes. PLoS One 13, e0194048.
D'Cruz AA, Speir M, Bliss-Moreau M, Dietrich S, Wang S, Chen AA, Gavillet M, Al-Obeidi A, Lawlor KE, Vince JE, Kelliher MA, Hakem R, Pasparakis M, Williams DA, Ericsson M, and Croker BA (2018). The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils. Sci Signal 11.
Liccardi G, Ramos Garcia L, Tenev T, Annibaldi A, Legrand AJ, Robertson D, Feltham R, Anderton H, Darding M, Peltzer N, Dannappel M, Schunke H, Fava LL, Haschka MD, Glatter T, Nesvizhskii A, Schmidt A, Harris PA, Bertin J, Gough PJ, Villunger A, Silke J, Pasparakis M, Bianchi K, and Meier P (2018). RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation. Mol Cell10.1016/j.molcel.2018.11.010.
O'Donnell JA, Lehman J, Roderick JE, Martinez-Marin D, Zelic M, Doran C, Hermance N, Lyle S, Pasparakis M, Fitzgerald KA, Marshak-Rothstein A, and Kelliher MA (2018). Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflam
mation and Autoimmunity. J Immunol 200, 737-748.
Taraborrelli L, Peltzer N, Montinaro A, Kupka S, Rieser E, Hartwig T, Sarr A, Darding M, Draber P, Haas TL, Akarca A, Marafioti T, Pasparakis M, Bertin J, Gough PJ, Bouillet P, Strasser A, Leverkus M, Silke J, and Walczak H (2018). LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat Commun 9, 3910.
Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jungst C, Siedek F, Vogel W, Klumper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Kruger M, Schauss A, Perner S, Pasparakis M, Buttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, and Reinhardt HC (2018). The Cdkn1a(SUPER) Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Rep 25, 1027-1039 e1026.
Zelic M, Roderick JE, O'Donnell JA, Lehman J, Lim SE, Janardhan HP, Trivedi CM, Pasparakis M, and Kelliher MA (2018). RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J Clin Invest 128, 2064-2075.
Jaco I, Annibaldi A, Lalaoui N, Wilson R, Tenev T, Laurien L, Kim C, Jamal K, Wicky John S, Liccardi G, Chau D, Murphy JM, Brumatti G, Feltham R, Pasparakis M, Silke J, and Meier P (2017). MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Mol Cell 66, 698-710 e5.
Kondylis V, Kumari S, Vlantis K, and Pasparakis M (2017). The interplay of IKK, NF-kappaB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev 277, 113-27.
Kumari S, and Pasparakis M (2017). Epithelial Cell Death and Inflammation in Skin. Curr Top Microbiol Immunol 403, 77-93.
O'Donnell JA, Lehman J, Roderick JE, Martinez-Marin D, Zelic M, Doran C, Hermance N, Lyle S, Pasparakis M, Fitzgerald KA, Marshak-Rothstein A, and Kelliher MA (2017). Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. J Immunol10.4049/jimmunol.1701229.
Saleh D, Najjar M, Zelic M, Shah S, Nogusa S, Polykratis A, Paczosa MK, Gough PJ, Bertin J, Whalen M, Fitzgerald KA, Slavov N, Pasparakis M, Balachandran S, Kelliher M, Mecsas J, and Degterev A (2017). Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-beta Synthesis Induced by Lipopolysaccharide. J Immunol 198, 4435-47.
Van TM, Polykratis A, Straub BK, Kondylis V, Papadopoulou N, and Pasparakis M (2017). Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis. J Clin Invest 127, 2662-77.
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Role of FADD and caspase-8 in the regulation of intestinal epithelial cell death and inflammation
Institute for Genetics - CECAD Research Center
CMMC - PI - B 09
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Institute for Genetics - CECAD Research Center
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Prof. Dr. med. Thomas Benzing
Chair of the CMMC
