Research teams are increasingly trying to use the body's own immune system to fight cancer. A new study by the University of Bonn (Germany) and research institutions in Australia and Switzerland shows the strategies used by tumor cells to escape such an attack. The method developed for this research contributes to a better understanding of the "arms race" between immune defenses and the disease. The results could help to improve modern therapeutic approaches. They have been published in the journal "Immunity".
Cancer cells differ from healthy body cells by their appearance, by their behavior, and by the genes that are active in them. Often this does not go unnoticed: the immune system registers that something is wrong and sends its troops to fight the tumor. But often this response is too weak to keep the cancer in check in the long term or to even destroy it.
Scientists have therefore been trying for many years to strengthen the immune system's defensive reaction. They do this in a similar way to a policeman releasing a trained canine unit, on the hunt for a fugitive. The role of the “sniffing” dogs is played by the cytotoxic T-cells: they can detect and kill sick or defective cells. For cancer therapy, the researchers are therefore looking for T-cells in patients that detect tumor antigens. They can then multiply these antigens and inject the patient again.
Unfortunately, many tumors have developed strategies that enable them to escape the immune system. "In our study, we investigated what these strategies look like and what this depends on," explains Dr. Maike Effern from the Institute of Experimental Oncology at the Bonn University Hospital (Germany). "We concentrated on melanoma cells, i.e. malign skin cancer."
There are different characteristics in which melanomas differ from healthy cells. A whole range of other genes are active in them. Each of them is a potential antigen for T-cells. But which one is particularly suited to trigger a strong and lasting immune response? In order to answer this question, the researchers invented a tricky method in their experimental model: they attached a kind of label to various genes that are active in the development of melanoma cells, thereby generating antigens. They then released a group of T-cells against the tumor cells, which recognized precisely this molecular label as a disease feature. Using this strategy, the researchers now investigated how the cancer cells reacted to being pursued by the immune system. In doing so, they found clear differences depending on the gene that was marked with such a label.
"When the T-cells were directed against genes responsible for melanoma-typical characteristics, we observed that the cancer cells changed their appearance and suppressed these genes over time," explains Effern's colleague Dr. Nicole Glodde. "In this way, they hid from the immune system."
Another gene investigated in the study, on the other hand, is essential for the tumor’s survival. It is therefore not so easy to down-regulate it and thus hide it. "In our view, this gene would, therefore, have the potential to induce a very effective T-cell response," Effern stresses. "Our work might open the way to more effective immune therapies," hopes Prof. Dr. Michael Hölzel, head of the Institute of Experimental Oncology at the Bonn University Hospital and member of the ImmunoSensation excellence cluster at the University of Bonn. "The method we have developed also enables us to better understand the processes by which cancer cells slip under the radar of the immune defence system".
Maike Effern, Nicole Glodde, Matthias Braun, Jana Liebing, Helena N. Boll, Michelle Yong, Emma Bawden, Daniel Hinze, Debby van den Boorn-Konijnenberg, Mila Daoud, Pia Aymans, Jennifer Landsberg, Mark J. Smyth, Lukas Flatz, Thomas Tüting, Tobias Bald, Thomas Gebhardt, Michael Hölzel: Adoptive T cell therapy targeting different gene products reveals diverse and context-dependent immune evasion in melanoma. Immunity DOI: https://doi.org/10.1016/j.immuni.2020.07.007