Breaching the Tumor Firewall

T cells with a regulatory function within the immune system respond differently to apoptosis triggers than T cells that mount the actual defense reaction (effector T cells). This has now been shown for the first time in investigations with human T cells* conducted by Dr. Benedikt Fritzsching jointly with colleagues of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and other collaborators of Heidelberg University. The findings may provide new approaches for treating cancer and autoimmune diseases.

By inhibiting the effect of other lymphocytes, regulatory T cells control how strong a defense reaction is. In mice, a surplus of effector T cells leads to autoimmune diseases, while a surplus of regulatory T cells promotes cancer development: The regulatory T cells suppress the effector T cells and prevent the body’s fight against a tumor. “The regulatory cells build a real firewall around the cancer cells. By destroying them selectively, we can tackle cancer better," said Fritzsching. The Heidelberg scientists have come a big step closer to this therapeutic approach: They have recently shown in cell cultures that programmed cell death, or apoptosis, can be triggered in freshly isolated human regulatory T cells by binding the CD95 ligand to the CD95 protein at the cell surface. In contrast, resting effector immune cells react by starting the suicide program only after repetitive stimulation of the T cell receptor, which is responsible for recognizing their specific antigen. This kind of stimulation does not have any effect in regulatory immune cells. “The difference in susceptibility to CD95-ligand mediated apoptosis may possibly be utilized for treatment. We now have the possibility to cause the regulatory T cells to commit suicide and thereby reduce their inhibitory effect on effector T cells, which are thus better able to induce a defense reaction against cancer," said Fritzsching, summarizing the results.

With a view to the future, Fritzsching stated: “We now possess the concept of a new weapon which we can try to use against cancer cells." There are plans to investigate soon in mice whether treatment with CD95 ligand proteins can induce cell death in the regulatory immune cells of an intact organism and, thus, breach the firewall around a tumor. Furthermore, the Heidelberg scientists are looking at autoimmune disorders such as multiple sclerosis. In collaboration with a working group headed by Professor Brigitte Wildemann at the Heidelberg Neurological University Hospital, they were recently able to show that the regulatory T cells of multiple sclerosis patients have a defect that considerably reduces their ability to inhibit defense cells against the body’s own structures.

* Benedikt Fritzsching, Nina Oberle, Nadine Eberhardt, Sabine Quick, Jürgen Haas, Brigitte Wildemann, Peter H. Krammer, and Elisabeth Suri-Payer: “Cutting Edge: In contrast to effector T cells CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death". Journal of Immunology, Vol. 175, No. 1, pp 32–36, July 1, 2005.