• sense clinically
  • think mechanistically
  • act interdisciplinarily
  • treat innovatively
  1. Home
  2. BSIO Faculty
  3. Principal Investigators
  4. Prof. Dr. med. Britta Siegmund | Research Group Leader

Prof. Dr. med. Britta Siegmund

Britta Siegmund Charité - Universitätsmedizin Berlin Hindenburgdamm 30 12200 Berlin


Phone: + 49 30 450 514343

https://gastro.charite.de/en/research/ag_siegmund/

Scientific Scope

T cell exhaustion and subsequent impaired functionality of T cells severely compromises anti-tumor immune responses and represents a major hurdle for cancer immune therapies. In many human tumors, infiltrating CD8+ T cells display an exhausted phenotype which is characterized by reduced or absent cytokine production of IL-2, TNFα and IFNγ, decreased cytotoxicity and diminished proliferative capacity upon antigen challenge. We have recently observed, that Store-operated Ca2+ entry (SOCE) mediated by ORAI and STIM proteins is the predominant Ca2+ influx pathway in T cells regulating the differentiation and function of T cells.   Importantly, we found that SOCE is required to prevent the cellular exhaustion of CD8+ T cells as deletion of STIM genes in mice results an induction of PD-1 and TIM-3 on CD8+ T cells. The observation that tumor-infiltrating CTL isolated from human melanoma and murine MC-38 colon carcinoma have reduced Ca2+ influx and consequently show impaired cytolytic function suggests that a dampened signaling strength of SOCE in tumor-infiltrating CD8+ T cells is a common feature of cancer-mediated immunosuppression resulting in disturbed anti-tumor immune responses and increased cellular exhaustion of tumor infiltrating CD8+ T cells. Therefore, we want to explore pharmacologic and genetic approaches to restore SOCE in tumor-infiltrating CD8+ T cells thereby ameliorating the functional capacity of tumor-infiltrating effector CD8+ T cells and by preventing the cellular exhaustion of tumor infiltrating cells, which might be used to induce or amplify anti-tumor immune responses in patients with unsatisfying response rates to currently available check point inhibitors.

Future Directions

Ultimately, we will utilize the molecular tools to modulate calcium flux to overcome T cell exhaustion and to (re)activate cytotoxic T cell tumor killing.

Group members

  • Britta Siegmund - Head
  • Carl Weidinger – PI
  • Lea-Maxie Haag - PI
  • Inka Freise - Technician
  • Julia Hecker – Post-Doc
  • Toka Omar – PhD student
  • Nadra Alzain – PhD student
  • Benjamin Jädicke – PhD student

Selected References

  1. Kramer, C., H. Rulff, J. F. Ziegler, P. W. Monch, N. Alzain, A. Addante, A. Kuppe, S. Timm, P. Schrade, P. Bischoff, R. Glauben, J. Durr, M. Ochs, M. A. Mall, M. Gradzielski, and B. Siegmund. Ileal mucus viscoelastic properties differ in Crohn's disease. Mucosal Immunol 2024. 17: 713-722. 10.1016/j.mucimm.2024.05.002

  2. Horn, V., C. A. Cancino, L. M. Steinheuer, B. Obermayer, K. Fritz, […], C. Weidinger, H. E. Mei, B. Siegmund, K. Thurley, and A. N. Hegazy. Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4(+) T Cells as Predictors for Response to Integrin alpha4beta7-Blocking Therapy in Inflammatory Bowel Disease. Gastroenterology 2024. 10.1053/j.gastro.2024.09.021

  3. Letizia, M., Y. H. Wang, U. Kaufmann, L. Gerbeth, A. Sand, M. Brunkhorst, P. Weidner, J. F. Ziegler, C. Bottcher, S. Schlickeiser, C. Fernandez, M. Yamashita, K. Stauderman, K. Sun, D. Kunkel, M. Prakriya, I. B. Researchers, A. Sanders, B. Siegmund, S. Feske, and C. Weidinger. Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease. EMBO Mol Med 2022. 14: e15687. 10.15252/emmm.202215687

  4. Lehmann, M., K. Allers, C. Heldt, J. Meinhardt, F. Schmidt, Y. Rodriguez-Sillke, D. Kunkel, M. Schumann, C. Bottcher, C. Stahl-Hennig, S. Elezkurtaj, C. Bojarski, H. Radbruch, V. M. Corman, T. Schneider, C. Loddenkemper, V. Moos, C. Weidinger, A. A. Kuhl, and B. Siegmund. Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8(+) T cells. Mucosal Immunol 2021. 14: 1381-1392. 10.1038/s41385-021-00437-z

  5. Ziegler, J. F., C. Bottcher, M. Letizia, C. Yerinde, H. Wu, I. Freise, Y. Rodriguez-Sillke, A. K. Stoyanova, M. E. Kreis, P. Asbach, D. Kunkel, J. Priller, I. Anagnostopoulos, A. A. Kuhl, K. Miehle, M. Stumvoll, F. Tran, B. Fredrich, M. Forster, A. Franke, C. Bojarski, R. Glauben, B. S. Loscher, B. Siegmund, and C. Weidinger. Leptin induces TNFalpha-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease. Nat Commun 2019. 10: 5629. 10.1038/s41467-019-13559-7