Gottfried Baier. Head of Division of Cell Genetics

Medical University of Innsbruck. Website

Division of Cell Genetics. Pharmacology and Genetics. Peter Mayr Straße 1A. 6020 Innsbruck

Reseach subject

T lymphocyte signaling, T helper cell differentiation, T cell effector functions, autoimmunity, cancer immunity, innovative immunological therapy concepts

Summary

Due to its biological complexity, cancer is still poorly understood. It has been shown both experimentally and epidemiologically that chronic inflammation can predispose individuals to cancer, and may additionally represent an inseparable aspect of clinically prevalent cancer entities. Therefore, the decoding of both tumour and immune cell functions in cancer progression will be of the utmost importance in combating this frequently incurable disease. My team and I were the first to reveal the lymphocyte-intrinsic PKC/ NR2F6/Cbl-b axis as an essential signalling node governing the complex host-tumour interactions at the crossroads between inflammation and cancer. Modulation of this lymphocyte-intrinsic signaling pathway renders CD4+ and CD8+ effector T cells capable of rejecting otherwise lethal tumour burdens and their metastases in experimental murine cancer model systems in vivo. Mechanistically, Nr2f6 as well as Cblb knockout mice thereby display an immune contexture at the tumour site that allows superior anti-tumour T cell responses, increasing the survival rates of tumour-bearing mice. Since it has already been established that cancer-mediated immune evasion can lead to T cell dysfunction, our data strongly suggest that T cell-based therapies could significantly benefit from modulation of this novel NR2F6/Cbl-b inhibitory signalling pathway. Such a strategy of intracellular NR2F6 and/or Cbl-b checkpoint-targeting will improve the efficacy and broaden the applicability of cancer immunotherapy regimens, and thus has the potential in the future to lead to prolonged patient survival.

Publications

• Siegmund K, Klepsch V, Hermann-Kleiter N, Baier G. Proof of Principle for a T Lymphocyte Intrinsic Function of Coronin 1A. J Biol Chem. 2016 Oct 14;291(42):22086-22092. PubMed PMID: 27566541; PubMed Central PMCID: PMC5063991.
• Hermann-Kleiter N, Klepsch V, Wallner S, Siegmund K, Klepsch S, Tuzlak S, Villunger A, Kaminski S, Pfeifhofer C, Gruber T, Wolf D, Baier G. The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance. Cell Rep. 2015 Sep 29;12(12):2072-85. doi: 10.1016/j.celrep.2015.08.035. PMID: 26387951; PubMed Central PMCID: PMC4594157.
• Gruber T, Hinterleitner R, Hermann-Kleiter N, Meisel M, Kleiter I, Wang CM, Viola A, Pfeifhofer-Obermair C, Baier G. Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells. J Mol Cell Biol. 2013 Dec;5(6):358-68. doi: 10.1093/jmcb/mjt017. PubMed PMID: 23709694.
• Meisel M, Hermann-Kleiter N, Hinterleitner R, Gruber T, Wachowicz K, Pfeifhofer-Obermair C, Fresser F, Leitges M, Soldani C, Viola A, Kaminski S, Baier G. The kinase PKCα selectively upregulates interleukin-17A during Th17 cell immune responses. Immunity. 2013 Jan 24;38(1):41-52. doi:10.1016/j.immuni.2012.09.021. PubMed PMID: 23290522; PubMed Central PMCID: PMC3556779.
• Hermann-Kleiter N, Meisel M, Fresser F, Thuille N, Müller M, Roth L, Katopodis A, Baier G. Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter. J Autoimmun. 2012 Dec;39(4):428-40. doi: 10.1016/j.jaut.2012.07.007. PubMed PMID: 22921335; PubMed Central PMCID: PMC3516707.