Williams Cancer Institute

Breaking Through Cancer’s Defense: A New Hope in Immunotherapy

Cancer’s greatest weapon is its ability to undermine our body’s defenses. Tumors have developed sophisticated mechanisms to suppress cytotoxic T cells, crucial for combating cancer. Groundbreaking research from the Technical University of Munich (TUM) and Ludwig-Maximilians-Universität München (LMU) Hospital has illuminated the exact processes by which tumors achieve this suppression. Published in *Nature*, this study provides deep insights into tumor-immune interactions and opens the door to innovative cancer immunotherapies.

Tumors often prevent immune cells from recognizing them as dangerous or render them inactive. Immunotherapies aim to counteract these tactics by boosting the immune system, especially T cells. Unfortunately, many cancer patients do not respond to these therapies. This has driven researchers to develop new strategies.

Dr. Jan Böttcher of TUM and Prof. Sebastian Kobold of LMU Klinikum München identified prostaglandin E2 as a crucial substance that tumors use to manipulate the immune system early in the immune response. Many cancer cells secrete high levels of prostaglandin E2, which binds to EP2 and EP4 receptors on specific immune cells. These stem-like T cells are essential for a successful immune response. However, prostaglandin E2 severely limits this process, causing the immune response to collapse and allowing the tumor to progress unchecked. By blocking the interaction between prostaglandin E2 and its receptors in tumor models, researchers found that the immune system could effectively combat tumors.

Current immunotherapies typically target later stages of the immune response, such as checkpoint inhibitor therapies that aim to reactivate fully differentiated cytotoxic T cells. This new research highlights the importance of intervening earlier. Preventing the effects of prostaglandin E2 on stem-like T cells allows them to differentiate into cytotoxic T cells within the tumor, enhancing the effectiveness of existing therapies. The study also suggests that blocking prostaglandin E2 could allow T cells to respond more effectively to both administered and naturally occurring IL-2 signals.

A follow-up study published in *Nature* confirms these findings. Researchers from the University Hospital of Lausanne collaborated with the Munich team to examine the effects of prostaglandin E2 on T cells from human tumor tissues. Their results showed that blocking prostaglandin E2 improved T cell expansion and their ability to fight cancer cells.

This breakthrough provides a concrete starting point for enhancing immunotherapies. Researchers worldwide are now challenged to develop strategies to neutralize the effects of prostaglandin E2, either by preventing its production in tumors or by making immune cells resistant to it. This could significantly improve outcomes for many cancer patients, providing new hope in the fight against this formidable disease.

Reference: Sebastian B. Lacher, Janina Dörr, Gustavo P. de Almeida, Julian Hönninger, Felix Bayerl, Anna Hirschberger, Anna-Marie Pedde, Philippa Meiser, Lukas Ramsauer, Thomas J. Rudolph, Nadine Spranger, Matteo Morotti, Alizee J. Grimm, Sebastian Jarosch, Arman Oner, Lisa Gregor, Stefanie Lesch, Stefanos Michaelides, Luisa Fertig, Daria Briukhovetska, Lina Majed, Sophia Stock, Dirk H. Busch, Veit R. Buchholz, Percy A. Knolle, Dietmar Zehn, Denarda Dangaj Laniti, Sebastian Kobold & Jan P. Böttcher. (24 April 2024). PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. https://doi.org/10.1038/s41586-024-07254-x


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