Tumors actively prevent the formation of immune responses by so-called cytotoxic T cells, which are essential in the fight against cancer. Researchers from the Technical University of Munich (TUM) and the Ludwig-Maximilians-Universität München (LMU) have discovered for the first time exactly how this happens. The study in the magazine. Nature provides rationale for new cancer immunotherapies and could make existing treatments more effective. A second article in Nature confirms the findings.
In cancer, tumors often impair the body’s immune response. For example, they can prevent immune cells from perceiving cancer cells as a threat or inactivate them. Immunotherapies aim to overcome these mechanisms and stimulate the immune system, particularly T cells. However, these therapies do not work for a large number of cancer patients. Researchers around the world are searching for causes and new counterstrategies.
The messenger substance stops the effector development of T cells in tumors
A team led by Dr. Jan Böttcher, research group leader at the TUM Institute of Molecular Immunology, and Prof. Sebastian Kobold, Deputy Director of the Department of Clinical Pharmacology at the LMU Klinikum München, has discovered that tumors They use a messenger substance to influence immune cells in an early phase of the immune response. Many cancer cells show increased secretion of the messenger substance prostaglandin E2. The researchers were able to show that prostaglandin E2 binds to EP2 and EP4, two receptors on the surface of certain immune cells.
These T cells, called stem cells, migrate from other areas of the body to the tumor. If the immune response is successful, they multiply in the tumor and become cytotoxic T cells that attack the cancer. “This whole process is very limited when tumors secrete prostaglandin E2 and this factor binds to the EP2 and EP4 receptors,” says Jan Böttcher. “The T cell response collapses and the tumor can progress.” If the researchers prevented the interaction between the messenger substance and the receptor in tumor models, the immune system was able to fight the tumors effectively.
Current therapies address a later point in the immune response.
“We have discovered a mechanism that influences the body’s immune response at a crucial stage,” says Jan Böttcher. “Many tumors prevent stem-like T cells from generating cytotoxic T cells in the tumor that could attack the cancer.”
Current immunotherapies aim to prevent cancer from turning off immune responses at a later stage. Checkpoint inhibitor therapies, for example, aim to release the blockage of fully differentiated cytotoxic T cells and “reactivate” them. Before the feared T cell exhaustion occurs, which other researchers are trying to prevent, differentiated T cells must also be present.
Increase the effectiveness of existing therapies.
“Current treatments would probably be more effective if the effects of prostaglandin E2 on stem-like T cells were blocked to allow their unhindered differentiation within the tumor tissue,” says Sebastian Kobold.
This applies similarly to recent approaches that rely on the IL-2 protein to stimulate T cells. The current study shows that as soon as prostaglandin E2 binds to the two receptors, T cells can no longer respond to IL-2. “We suspect that even the body’s own IL-2 signals may be sufficient for T cells to successfully fight cancer once the effects of prostaglandin E2 have stopped,” says Sebastian Kobold.
The second study in “Nature” confirms the results
A second research publication in Nature investigates the effects of prostaglandin E2 on the immune system. For this study, the authors, researchers from the University Hospital of Lausanne, collaborated with the Munich team. In their laboratory they examined, among other things, T cells from human tumor tissue. When they blocked the release of prostaglandin E2 in the cancer tissue, the T cells showed better expansion and were therefore able to fight human cancer cells more effectively.
The search for counterstrategies begins
“We now have a concrete starting point to significantly improve immunotherapies,” says Jan Böttcher. “Researchers around the world must now develop strategies to overcome tumor defense. We need to stop the effects of prostaglandin E2, either by preventing tumors from producing the molecule or by making immune cells resistant to it.”