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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.
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.
- Carl Weidinger - Postdoc/PI
- Inka Freise - Technician
- Hsiang-Jung Hsiao - PhD student
- Cansu Yerinde - PhD student
- Marilena Letizia - PhD student
- Julia Hecker - PhD student
- 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. 2019 Leptin induces TNFalpha-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease. Nat Commun 10: 5629
- Elling, R., B. Keller, C. Weidinger, M. Haffner, S.D. Deshmukh, I. Zee, C. Speckmann, S. Ehl, K. Schwarz, S. Feske, and P. Henneke. 2016 Preserved effector functions of human ORAI1- and STIM1-deficient neutrophils. J Allergy Clin Immunol 137: 1587-1591 e1587
- Desvignes, L., C. Weidinger, P. Shaw, M. Vaeth, T. Ribierre, M. Liu, T. Fergus, L. Kozhaya, L. McVoy, D. Unutmaz, J.D. Ernst, and S. Feske. 2015. STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. J Clin Invest 125: 2347-2362
- Shaw P #, Weidinger C #, Kluethy K, Kaech S and Feske S., STIM1 and STIM2 control antiviral immunity by CD4 and CD8 T cells, J Clin Invest., 2014, Oct; 124 (10): 4549-63 # both authors contributed equally to this study
- Weidinger C, Shaw P and Feske S. STIM1 and STIM2 mediated Ca2+ influx regulates antitumor immunity by CD8+ T cells. Embo Molecular Medicine, 2013 Sep;5(9): 1311- 21