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Project P12

Kathi_2 

Dr. Kathrin Renner-Sattler

Internal Medicine III

University Medical School Regensburg

Kathrin.Renner-Sattler@ukr.de

 Wolfgang_2

Prof. Dr. Wolfgang Herr

Internal Medicine III 

University Medical School Regensburg

Wolfgang.Herr@ukr.de

 

Topic:

Impact of drugs targeting tumor metabolism on human CD8 T cell effector functions

Summary

Cancer and leukemia cells display a strongly elevated glucose and glutamine metabolism and altered mitochondrial function compared to normal cells. The inhibition of those vital metabolic pathways diminishes the proliferation and viability of cancer cells and the secretion of immunosuppressive metabolites. Recent studies, however, suggest that the metabolic phenotype of activated immune cells, especially of T cells, shows similarities to that of cancer cells. Hence the application of drugs inhibiting metabolic pathways considered as essential for both cell types might impede endogenous and therapeutically induced immune responses, thereby adversely affecting patient outcome. However, the interaction between metabolism and effector functions of CD8+ T cells is not well elucidated, particularly in the human system. In the proposed project we will initially characterize the metabolic phenotype of primary human CD8+ T cell subsets (naïve, central memory, effector memory) and in vitro generated leukemia-reactive CD8+ cytotoxic T lymphocytes (CTL) in detail. Furthermore, we will analyze the impact of glycolytic inhibition by diclofenac or monocarboxylate transporter 1/2, mitochondrial inhibition by metformin or pioglitazone, and tyrosine kinase inhibition by sorafenib on effector functions of the aforementioned CD8+ T cell populations in vitro. The in vivo impact on effector functions of human leukemia-reactive CD8+ CTL will be investigated in leukemia bearing NSG mice, with main focus on the most promising and clinically relevant drug candidates. The major objective of the proposed project is the detailed characterization of the interaction between metabolically active drugs and human CD8+ T cell function. The results should allow the identification of immunosuppressive interactions but also potential synergisms in order to improve the effectivity of cancer therapies.  

 

References

1. 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. 

2. 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.

3. Fischer, K., P. Hoffmann, S. Voelkl, N. Meidenbauer, J. Ammer, M. Edinger, E. Gottfried, S. Schwarz, G. Rothe, S. Hoves, K. Renner, B. Timischl, A. Mackensen, L. Kunz-Schughart, R. Andreesen, S.W. Krause, and M. Kreutz. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007 109(9):3812-3819.

4. Eberhart, K., K. Renner, I. Ritter, M. Kastenberger, K. Singer, C. Hellerbrand, M. Kreutz, R. Kofler, and PJ. Oefner. Low doses of 2-deoxy-glucose sensitize acute lymphoblastic leukemia cells to glucocorticoid-induced apoptosis. Leukemia. 2009 23(11):2167-2170. First two authors contributed equally.

5. Dietl, K*., K. Renner*, B. Timischl, K. Dettmer, K. Eberhart, C. Dorn, C. Hellerbrand, L. Kunz-Schughart, P.J. Oefner, R. Andreesen, M. Kreutz, and E. Gottfried. Lactic acid inhibits the glycolytic flux in human monocytes-impact on cytokine secretion. J Immunol. 2010 184(3):1200-1209. *First two authors contributed equally

6. Albrecht, J., M. Frey, D. Teschner, A. Carbol, M. Theobald, W. Herr*, and E. Distler*. 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

7. Distler, E., A. Bloetz, J. Albrecht, S. Asdufan, A. Hohberger, M. Frey, E. Schnurer, S. Thomas, M. Theobald, U. F. Hartwig, and W. Herr. Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells. Haematologica. 2011 96(7):1024–1032.

8. Gottfried E, Lang SA  (P6), Bosserhoff AK, Gronwald W (CP), …, Hau P, Dettmer K (CP)Oefner PJ (P7), Andreesen R, Kreutz M (P1). Diclofenac targets glycolysis via MYC and HIF regulation. PLOS ONE 2013 Jul 9;8(7). 

9. Schmidl C, Renner K, Eder R, Peter K, Timo Lassmann T, Balwierz PJ, Itoh M, Nago-Sato S, Kawaji H, Carninci P, Suzuki H, Hayashizaki A, Andreesen R, Hume DA, Hoffmann P, Forrest ARR, Kreutz M, Edinger M, Rehli M, for the FANTOM consortium. Transcription and enhancer profiling in human monocyte subsets. Blood 2014 24;123(17).

10. Krupar R, Robold K, Gaag D, Spanier G, Kreutz MRenner KHellerbrand C, Hofstaedter F, Bosserhoff AK. Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different. Virchows Arch. 2014 Sep;465(3):299-312.

11. Peter K, Rehli M, Singer K, Renner KKreutz M. Lactic acid delays the inflammatory response of human monocytes. BBRC 2015  in press

Co-workers

Steffi_2                   Christina Bruss_2  

Stephanie Färber

Stephanie.Faerber@ukr.de

 Christina Bruss

Christina.Bruss@ukr.de

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