New insights into cell communication in the immune response to cancer
In addition to traditional chemotherapy, researchers are developing innovative cancer treatments that help patients’ immune systems fight cancer on their own. These treatments are gentler on patients than conventional therapies. Until now, it was unclear exactly how communication works between different types of immune cells, including CD4⁺ T cells—which use signaling molecules to control the activation of other immune cells—and CD8⁺ T cells, which can kill cancer cells. We spoke with Prof. Dr. Birgit Sawitzki about the study in which her team deciphered how these cells work together in response to lung adenocarcinoma.
What problem were you trying to solve with this research project?
It was already known that CD4⁺ T cells can support CD8⁺ T cells. This occurs primarily through soluble factors such as cytokines—that is, proteins that regulate cell growth and differentiation—or indirectly via antigen-presenting cells. However, it was unclear whether this support also occurs through direct cell-to-cell communication via specific ligand-receptor interactions, i.e., through molecules on the cell surface. It was precisely this direct form of communication that we wanted to investigate.
What is the significance of the communication axis between CD4⁺ and CD8⁺ T cells in the immune response to lung tumors?
Our results show that CD4⁺ and CD8⁺ T cells interact directly with each other via the AICL–KLRF1 axis. This is a signaling pathway whose significance has previously been described mainly for natural killer cells. This interaction helps maintain cytokine production by CD8⁺ T cells which is their ability to produce inflammatory mediators such as IFN-γ and TNF. This is particularly relevant for the subset of CD8⁺ T cells that are in an early stage of exhaustion and still retain residual function. The AICL–KLRF1 axis thus represents an additional mechanism through which CD4⁺ T cells can support the immune response of CD8⁺ T cells.
Are there differences in the presence of these T cells between tumorous and healthy tissues, and what are the consequences of this?
Yes, we observe clear differences: Both AICL⁺ CD4⁺ T cells and KLRF1⁺ CD8⁺ T cells are found primarily in non-tumorous tissue and are significantly less common in the tumor. This spatial separation is accompanied by reduced cytokine production. This suggests that important supportive signals between T cells are lost in the tumor microenvironment, thereby contributing to the functional weakening of the immune response.
What surprised you, and if so, why? What was new?
It was surprising that a ligand-receptor interaction between T cells, which had previously been little studied, is actually functionally relevant. What is particularly new is that we were able to show that this direct communication between CD4⁺ and CD8⁺ T cells exists, contributes to the maintenance of their function, and is impaired within the tumor.
How do patients benefit from this research?
Our findings provide new insights into why T cells lose their function within the tumor. In the long term, this knowledge could help make immunotherapies more effective. Furthermore, it opens up the possibility of specifically targeting this form of T cell communication therapeutically to enhance the activity of tumor-fighting T cells.