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Project P9

Simone_2 Dr. Simone ThomasInternal Medicine III University Medical School Regensburg Simone.Thomas@ukr.de
Wolfgang_2 Prof. Dr. Wolfgang HerrInternal Medicine III University Medical School Regensburg Wolfgang.Herr@ukr.de
Foto-Prof.-Marina-P.-Kreutz Prof. Dr. Marina P. KreutzInternal Medicine III University Medical School Regensburg Marina.Kreutz@ukr.de

Topic: IDH mutations in the interplay of metabolism and antileukemic immune response Summary Adoptive transfer of cytotoxic T lymphocytes (CTL) as well as vaccination with leukemia antigens are potent strategies to improve immunosurveillance against leukemias. Recently, mutations (Mut) in the genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 have been detected in acute myeloid leukemia (AML) blasts of up to 20% of patients. IDH mutations induce a neomorphic function to produce the oncometabolite 2-hydroxyglutarate (2-HG), which can alter many cellular processes upon inhibition of a-ketoglutarate dependent dioxygenases (e.g. DNA demethylases). We have previously established in vitro protocols to reliably generate leukemia reactive CD4+ and CD8+ CTL from HLA-matched naive T-cell precursors upon stimulation with patient-derived primary leukemia cells. In the submitted project we will investigate T-cell responses against IDHMut 1 and 2. For this, we will stimulate CD4+ and CD8+ T cells from AML patients and healthy donors against IDHMut proteins and predicted IDHMut peptide epitopes. To analyze the biological relevance of IDHMut specific T cells, we will adoptively transfer T-cell clones into AML engrafted immunodeficient NOD/SCID/IL2Rgcnull (NSG) mice. In the second part of the project, we will investigate the effect of 2-HG on human dendritic cells (DC) and T cells. Here, our preliminary data show that 2-HG decreases the secretion of IL-12 in DCs, which possibly impairs T-cell activation. The underlying mechanism of this effect will be further analyzed (e.g. transcriptional regulation of cytokine secretion). Our hypothesis is that IDHMut specific T cells are potent leukemia-specific effectors in adoptive immunotherapy of IDHMut+ AML. Specific elimination of leukemia blasts would also reduce 2-HG levels in patients, which potentially would further strengthen antileukemia immunity. References Dorrschuck, A., A. Schmidt, E. Schnurer, M. Gluckmann, C. Albrecht, C. Wolfel, V. Lennerz, A. Lifke, C. Di Natale, E. Ranieri, L. Gesualdo, C. Huber, M. Karas, T. Wolfel, and W. Herr CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib-associated renal carcinoma antigens with ubiquitous or restricted tissue expression. Blood 2004 104(8): 2591–2599. Kausche, S., T. Wehler, E. Schnurer, V. Lennerz, W. Brenner, S. Melchior, M. Grone, M. Nonn, S. Strand, R. Meyer, E. Ranieri, C. Huber, C. S. Falk, and W. Herr Superior antitumor in vitro responses of allogeneic matched sibling compared with autologous patient CD8+ T cells. Cancer Res. 2006 66(23): 11447–11454. Gottfried, E., L. A. Kunz-Schughart, S. Ebner, W. Mueller-Klieser, S. Hoves, R. Andreesen, A. Mackensen, and M. Kreutz Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 2006 107(5): 2013–2021. Dietl, K., K. Renner, K. Dettmer, B. Timischl, K. Eberhart, C. Dorn, C. Hellerbrand, M. Kastenberger, L. A. Kunz-Schughart, P. J. Oefner, R. Andreesen, E. Gottfried*, and M. P. Kreutz* Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol. 2010 184(3): 1200–1209. *Shared senior authorship Voss, R.-H.*, S. Thomas*, C. Pfirschke, B. Hauptrock, S. Klobuch, J. Kuball, M. Grabowski, R. Engel, P. Guillaume, P. Romero, C. Huber, P. Beckhove, and M. Theobald Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells. Blood. 2010 115(25): 5154–5163. *Shared first authorship Albrecht, J., M. Frey, D. Teschner, A. Carbol, M. Theobald, W. Herr*, and E. Distler*. 2011. IL-21-treated naive CD45RA+ CD8+ T cells represent a reliable source for producing leukemia-reactive cytotoxic T lymphocytes with high proliferative potential and early differentiation phenotype. Cancer Immunol Immunother. 2011 60(2): 235–248. *Shared senior authorship  Mendler, A.N., B. Hu,  P.U. Prinz, M. Kreutz, E. Gottfried, E. Noessner Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation.  Int J Cancer. 2011 1;131(3):633-40 Thomas, S., S. Klobuch, K. Besold, B. Plachter, J. Dorrie, N. Schaft, M. Theobald, and W. Herr 2012. Strong and sustained effector function of memory- versus naive-derived T cells upon T-cell receptor RNA transfer: implications for cellular therapy. Eur J Immunol. 2012 42(12): 3442–3453. Thomas, S., S. Klobuch, M. Sommer, R. van Ewijk, M. Theobald, R. G. Meyer, and W. Herr Human CD8(+) memory and EBV-specific T cells show low alloreactivity in vitro and in CD34(+) stem cell-engrafted NOD/SCID/IL-2Rgammac(null) mice. Exp Hematol. 2014 42(1): 28-38.e2.   Co-workers

Sebastian_2      Kathrin Hammon2 Max_Schmid_homepage

Sebastian Klobuch

Sebastian Klobuch@ukr.de

 Kathrin Hammon


 Maximilian Schmied