Inhibition of tumor-associated Regulatory T cells by microbial metabolites

Abstract:

In this project we want to investigate the therapeutic targeting of regulatory T cells (Tregs) with microbial metabolites in the cancer setting. As tumor cells can induce and propagate an immunosuppressive microenvironment, the expansion of Tregs in the tumor is still a leading cause of therapy failure. We plan to demonstrate that novel small bacteria-derived molecules can be used to manipulate the function and differentiation of Tregs in the tumor in favor of the host. In this project we want to investigate one such microbial metabolite and its effect on Tregs in vitro and in vivo.

Principal investigator:

Univ.-Prof. Dr. med. Tim Sparwasser
Institut für Medizinische Mikrobiologie und Hygiene
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Obere Zahlbacher Str. 67, 55131 Mainz
Phone: +49 (0)6131 17-9363
E-mail: sparwasser@uni-mainz.de
Web: https://www.unimedizin-mainz.de/medizinische-mikrobiologie-und-hygiene/forschung/infection-immunology-sparwasser-laboratory.html

Postdoc:

Dr. rer. nat. Panagiota Mamareli

Doctoral candidate:

Fatima Al-Naimi

Project-related publications:

Raud B., Roy D.G., Divakaruni AS, Tarasenko TN, Franke R, Ma EH, Samborska B, Hsieh WY, Wong AH, Stuve P, Arnold-Schrauf C, Guderian M, Lochner M, Rampertaap S, Romito K, Monsale J, Bronstrup M, Bensinger SJ, Murphy AN, McGuire PJ, Jones RG, Sparwasser T*, and Berod L*. (2018) Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation. Cell Metab 28:504-515 e507. *equal contribution

Almeida L, Lochner M, Berod L, Sparwasser T (2016) Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 28:514-524.

Lochner M, Berod L, Sparwasser T (2015) Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 36:81-91.

Berod, L., C. Friedrich, A. Nandan, J. Freitag, S. Hagemann, K. Harmrolfs, A. Sandouk, C. Hesse, C.N. Castro, H. Bahre, S.K. Tschirner, N. Gorinski, M. Gohmert, C.T. Mayer, J. Huehn, E. Ponimaskin, W.R. Abraham, R. Muller, M. Lochner, and Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20:1327-1333.

Pace, L., A. Tempez, C. Arnold-Schrauf, F. Lemaitre, P. Bousso, L. Fetler, Sparwasser T, and S. Amigorena (2012) Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 338:532-536.

Mayer, C.T., A.A. Kuhl, C. Loddenkemper, and Sparwasser T (2012) Lack of Foxp3+ macrophages in both untreated and B16 melanoma-bearing mice. Blood 119:1314-1315.

Klages, K., C.T. Mayer, K. Lahl, C. Loddenkemper, M.W. Teng, S.F. Ngiow, M.J. Smyth, A. Hamann, J. Huehn, and Sparwasser T (2010) Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70:7788-7799.

Kim, J., K. Lahl, S. Hori, C. Loddenkemper, A. Chaudhry, P. deRoos, A. Rudensky, and Sparwasser T (2009) Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. J Immunol 183:7631-7634.

Heit, A., F. Gebhardt, K. Lahl, M. Neuenhahn, F. Schmitz, F. Anderl, H. Wagner, Sparwasser T*, D.H. Busch*, and K. Kastenmuller* (2008) Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. Eur J Immunol 38:1585-1597. *equal contribution