Tumors actively prevent the formation of immune responses by so-called cytotoxic T cells, which could fight cancer. Researchers at the Technical University of Munich (TUM) and the University Hospital of Ludwig Maximilian University of Munich (LMU) are now describing for the first time how this happens. The study in the journal “Nature” provides starting points for new cancer immunotherapies and could make existing treatments more effective. A second paper in “Nature” confirms the findings.
Messenger substance stops further development of T cells in the tumor
A team led by Dr. Jan Böttcher, research group leader at the Institute for Molecular Immunology at TUM, and Prof. Sebastian Kobold, deputy director of the Department of Clinical Pharmacology at LMU University Hospital Munich, has now discovered that tumors influence immune cells in an early phase of the immune response using a messenger substance. Many cancer cells increasingly secrete the messenger substance prostaglandin E2. The researchers were able to demonstrate that prostaglandin E2 binds to EP2 and EP4, two receptors on the surface of certain immune cells.
These so-called stem cell-like T cells migrate from other areas of the body into the tumor. In a successful immune response, they multiply there and develop into cytotoxic T cells that attack the cancer. “All of this is slowed down when tumors secrete prostaglandin E2 and it binds to the EP2 and EP4 receptors,” says Jan Böttcher. “The T cell response collapses, so to speak, and the tumor can grow unimpeded.” When the researchers prevented the interaction of the messenger substance and receptor in tumor models, the immune system was able to effectively fight tumors.
Publikationen:
S.B. Lacher, J. Dörr, G. P. de Almeida, J. Hönninger, F. Bayerl, A. Hirschberger, A.-M. Pedde, P. Meiser, L. Ramsauer, T.J. Rudolph, N. Spranger, M. Morotti, A. J. Grimm, S. Jarosch, A. Oner, L. Gregor, S. Lesch, S. Michaelides, L. Fertig, D. Briukhovetska, L. Majed, S. Stock, D.H. Busch, V.R. Buchholz, P.A. Knolle, D. Zehn, D. Dangaj Laniti, S. Kobold, J.P. Böttcher, „Prostaglandin E2 curtails interleukin-2-dependent effector expansion from tumour infiltrating stem-like CD8+ T cells to promote cancer immune escape“. Nature (2024). DOI: 10.1038/s41586-024-07254-x.
M. Morotti, A.J. Grimm, H. Carrasco Hope, M. Arnaud, M. Desbuisson, N. Rayroux, D. Barras, M. Masid, B. Murgues, B.S. Chap, M. Ongaro, I.A. Rota, C. Ronet, A. Minasyan, J. Chiffelle, S.B. Lacher, S. Bobisse, C. Murgues, E. Ghisoni, K. Ouchen, R. Bou Mjahed, F. Benedetti, N. Abdellaoui, R. Turrini, P.O. Gannon, K. Zaman, P. Mathevet, L. Lelievre, I. Crespo, M. Conrad, G. Verdeil, L. E. Kandalaft, J. Dagher, J. Corria-Osorio, M.-A. Doucey, P.-C. Ho, A. Harari, N. Vannini, J.P. Böttcher, D. Dangaj Laniti, and G. Coukos. “ PGE2 inhibits TIL expansion by disrupting IL-2 signalling and metabolism“. Nature (2024). DOI: 10.1038/s41586-024-07352-w.
