• sense clinically
  • think mechanistically
  • act interdisciplinarily
  • treat innovatively

Prof. Dr. med. Britta 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

  • Carl Weidinger - Postdoc/PI
  • Inka Freise - Technician
  • Hsiang-Jung Hsiao - PhD student
  • Cansu Yerinde - PhD student
  • Marilena Letizia - PhD student
  • Julia Hecker - PhD student

Selected References