Prof. Dr. med. Britta Siegmund
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
- Atreya, R., Siegmund, B. (2021) "Location is important: differentiation between ileal and colonic Crohn’s disease." Nat Rev Gastro Hepatol 2021 doi: 10.1038/s41575-021-00424-6.
- Wu, H., Han, Y., Rodriguez-Silke,Y., Deng, H., Siddiqui, S., Treese, C., Schmidt, F., Friedrich, M., Keye, J., Wan, J., Qin, Y., Kühl, A.A., Qin, Z., Siegmund, B.*, Glauben, R*.(2019) "Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages." EMBO Mol Med 2019 11(11):e10698.
- Ziegler, J., Boettcher, C., Letizia, M., Cansu, Y., Wu, H., Freise, I., Rodriguez-Sillke, Y., Stoyanova, A., Kreis, M., Asbach, P., Kunkel, D., Priller, J., Anagostopoulos, I., Kuehl, A., Miehle, K., Sturmvoll, M., Tran, F., Fredrich, B., Fordter, M., Franke, A., Bojarski, C., Glauben, R., Löscher, B.S., Siegmund, B.*, Weidinger, C.* (2019) "Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease." Nat Commun 2019, 10(1):5629.
- Kredel, L.I., Batra, A., Stroh, T., Kühl, A.A., Zeitz, M., Erben, U., Siegmund, B. (2013) "Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease." Gut 2013, 62:852-62.
- Glauben, R., Batra, A., Stroh, T., Erben, U., Fedke, I., Lehr, H.A., Leoni, F., Mascagni, P., Dinarello, C.A., Zeitz, M., Siegmund, B.(2008) "Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice." Gut 2008 May;57(5):613-22. doi: 10.1136/gut.2007.134650.