Tumor cells slow down immune defence

A team led by Dr Jan Böttcher, research group leader at the Institute of Molecular Immunology at the Technical University of Munich and DZL researcher Prof. Sebastian Kobold, Deputy Director of the Department of Clinical Pharmacology at LMU Hospital Munich, has shown that a messenger substance of tumor cells slows down so-called cytotoxic T cells in an early phase of the immune response. The messenger substance is prostaglandin, which is increasingly released by many tumor cells.

Prostaglandin binds to receptors on the surface of specific immune cells, the so-called stem cell-like T cells. In a functioning immune response, these immune cells migrate into the tumor, multiply there and develop into cytotoxic T cells that attack the cancer. Prostaglandin prevents this development, so the T-cell response collapses, and the tumor can grow unhindered.

If the researchers blocked the interaction between prostaglandin and the receptor on the surface of the immune cells in tumor models, the immune system could effectively combat tumors.

Starting point in the early phase of the immune response

"We have discovered a mechanism that influences the body's immune defence in a crucial phase," says Jan Böttcher. "Many tumors prevent the stem cell-like T cells from forming cytotoxic T cells in the tumor that could attack the cancer."

Current therapies start at a later stage of the immune response, for example, by releasing the blockade of fully differentiated cytotoxic T cells (checkpoint inhibitor therapies) and "switching them back on." Treatment concepts to prevent T cell exhaustion also affect already differentiated T cells.

Improving the effect of existing therapies

"Today's treatment approaches would probably be more effective if the effects of prostaglandin E2 on stem cell-like T cells were blocked so that they can differentiate unhindered in the tumor," says Sebastian Kobold.

This applies to recent approaches that stimulate T cells with the protein Interleukin 2 (IL-2). The current study shows that when the prostaglandin E2 binds to the two receptors, T cells no longer react to IL-2. "We suspect that even the body's own IL-2 signals may be sufficient to enable T cells to successfully fight cancer as soon as the effects of prostaglandin E2 have been stopped," says Sebastian Kobold.

Strategies to circumvent tumor defence

"We now have a concrete starting point for significantly improving immunotherapies," says Jan Böttcher. "Now researchers worldwide need to develop strategies to circumvent the tumors’ defences. We need to stop the effects of prostaglandin E2 - either by preventing tumors from producing the molecule or by making immune cells insensitive to it."

Source: Press release of the TUM

Original publication: 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.