TP01 Bopp/Schmitt

ICER-steered transcriptional regulation in macrophage-driven immune evasion mechanisms of malignant melanoma

Abstract:

Tumor growth and progression is based on mechanisms to avoid efficient anti-tumor immune responses. Inter alia, tumors pursue the strategy to exploit immune suppressive mechanism by attracting or inducing CD4+FOXP3+ regulatory T cells (Tregs) and non-inflammatory macrophages of the M2-like phenotype. Therefore, the transient abolishment of immune cell-mediated suppression represents promising options for tumor therapy.
In this context, others and we demonstrated an important role for cAMP and cAMP-induced expression of ICER in the maintenance of peripheral tolerance. Our preliminary analyses of Icer-deficient (Icer-/-) mice revealed efficient tumor eradication in a preclinical B16F10 melanoma model. Detailed analyses employing conditional deletion approaches of Icer demonstrated a crucial contribution of ICER expression to tumor immune evasion specifically in myeloid cells/macrophages (Lysm-Cre). Interestingly and in contrast to melanomas, growth and progression of colon adenocarcinomas (MC38) was not affected in Icer-/- mice, suggesting variable immune evasion strategies in different tumors. Hence, this project is focused on the mrlanoma- and ICER-specific immune evasion.

Principal investigators:

Univ.-Prof. Dr. rer. nat. Tobias Bopp
Institut für Immunologie
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17-6175
E-mail: boppt@uni-mainz.de
Web: http://www.unimedizin-mainz.de/immunology/laboratories/boppschmitt-laboratory.html?L=1

Univ.-Prof. Dr. rer. nat. Edgar Schmitt
Institut für Immunologie
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17-6195
E-mail: eschmitt@uni-mainz.de
Web: http://www.unimedizin-mainz.de/immunology/laboratories/boppschmitt-laboratory.html?L=1

Doctoral candidates:

Natalia Truong-Andrievici

 

Project-related publications:

Bacher N, Raker V, Hofmann C, Graulich E, Schwenk M, Baumgrass R, Bopp T, Zechner U, Merten L, Becker C & Steinbrink K (2013) Interferon-alpha suppresses cAMP to disarm human regulatory T Cells. Cancer Research 73: 5647-5656

Bodor J, Bopp T, Vaeth M, Klein M, Serfling E, Hünig T, Becker C, Schild H & Schmitt E (2012) Cyclic AMP underpins suppression by regulatory T cells. European Journal of Immunology 42: 1375-1384 (review)

Klein M, Vaeth M, Scheel T, Grabbe S, Baumgrass R, Berberich-Siebelt F, Bopp T, Schmitt E* & Becker C* (2011) Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells. The Journal of Immunology 188: 1091-1097 (*Joint senior author)

Vaeth M*, Gogishvili T*, Bopp T*, Klein M, Berberich-Siebelt F, Gattenloehner S, Avots A, Sparwasser T, Grebe N, Schmitt E, Hunig T, Serfling E & Bodor J (2011) Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). Proceedings of the National Academy of Sciences 108: 2480-2485 (*Contributed equally)

Dehzad N*, Bopp T*, Reuter S, Klein M, Martin H, Ulges A, Stassen M, Schild H, Buhl R, Schmitt E & Taube C (2011) Regulatory T Cells More Effectively Suppress Th1-Induced Airway Inflammation Compared with Th2. The Journal of Immunology 186: 2238-2244 (*Contributed equally)

Lahl K, Mayer C, Bopp T, Huehn J, Loddenkemper C, Eberl G, Wirnsberger G, Dornmair K, Geffers R, Schmitt E, Buer J & Sparwasser T (2009) Nonfunctional Regulatory T Cells and Defective Control of Th2 Cytokine Production in Natural Scurfy Mutant Mice. The Journal of Immunology 183: 5662-5672

Becker C, Taube C, Bopp T, Becker C, Michel K, Kubach J, Reuter S, Dehzad N, Neurath M, Reifenberg K, Schneider F, Schmitt E & Jonuleit H (2009) Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells. Blood 114: 1263-1269

Bopp T, Dehzad N, Reuter S, Klein M, Ullrich N, Stassen M, Schild H, Buhl R, Schmitt E* & Taube C* (2009) Inhibition of cAMP Degradation Improves Regulatory T Cell-Mediated Suppression. The Journal of Immunology 182: 4017-4024 (*Joint senior authors)

Bopp T, Becker C, Klein M, Klein-Heßling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege M, Stassen M, Jonuleit H & Schmitt E (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell–mediated suppression. The Journal of Experimental Medicine 204: 1303-1310

Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C, Klein M, Schild H, Schmitt E* & Stassen M* (2005) NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+T lymphocytes by CD4+CD25+regulatory T cells. The Journal of Experimental Medicine 201: 181-187 (*Joint senior authors)