Activated T cells that carry a certain marker protein on their surface are controlled by natural killer (NK) cells, another type of immune system cell. In this way, the body supposedly stops destructive immune reactions. Researchers from the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim (UMM) have now discovered that NK cells can thus alter the effect of cancer therapies with immune checkpoint inhibitors (ICIs). . They could also be responsible for the rapid decline of therapeutic CAR-T cells. Interventions in this mechanism could potentially improve the efficacy of these cellular immunotherapies against cancer.
The T cells of the immune system are the main actors in the defense against viral infections and tumor cells. On the other hand, they attack the body’s own healthy tissue through autoimmune reactions that can even be fatal. Therefore, the body must maintain strict control over the activity of T cells.
A large number of molecules and messengers are involved in the very complex regulation of T cell activity. Only recently have researchers discovered that another group of immune cells contributes to the control of T cell activity. Natural killer cells (NK cells) are part of innate immunity, that is, the rapid response force that detects and eliminates quickly remove infected or malignant cells.
“Studies have shown that NK cells can also destroy activated T cells and thus limit their proliferation,” says Michael Platten, head of the department at the DKFZ and director of the University Clinic of Neurology in Mannheim. “However, until now we did not know what characteristic characterizes T cells as targets of NK cells.”
By examining activated T cells from healthy donors, Platten’s team identified the B7H6 protein as a recognition molecule for NK cell attacks in a new study. Activated T cells from the blood of patients with autoimmune diseases, cancer or viral infections expose large amounts of B7H6 on their surface. Coculture experiments in the culture plate showed that NK cells recognize activated T cells by their expression of B7H6. In contrast, T cells whose B7H6 gene was destroyed with CRISPR-Cas were protected from lethal attack by NK cells.
“The elimination of T cells by NK cells is triggered by a mechanism intrinsic to T cells. Activated T cells are temporarily identified as targets for NK-induced cell lysis,” explains Michael Kilian, first author of the publication. , and adds: “This may limit the activation and excessive expansion of T cells as a control mechanism to curb destructive immune responses.”
Immune checkpoint inhibitor therapies are neutralized by NK cells
“We now know a number of molecules called checkpoints, which reduce or enhance the activation of T cells and thus modulate the course of immune reactions. B7H6 can now be classified as another inhibitory immune checkpoint cell. T,” explains Platten, leader of the study. .
Some widespread cancer therapies with drugs from the checkpoint inhibitor (ICI) group target certain checkpoint inhibitor molecules. They activate the immune system against the tumor by releasing the immune brakes. Could B7H6-mediated elimination of tumor-reactive T cells counteract the effect of ICI cancer immunotherapy? The researchers tested this using tissue samples from esophageal cancer patients who had received ICI therapy. Those patients who had not responded to ICI had a higher number of NK cells in the tumor tissue and, in fact, had a shorter progression-free survival time.
Cellular immunotherapy is more effective in the absence of NK cells
Cellular immunotherapies are becoming increasingly important in cancer medicine. For example, some forms of blood cancer are currently often treated with so-called CAR-T cells, which are equipped with personalized anti-cancer receptors. However, the success of the therapy is usually limited as the number of therapeutic cells in the patient’s body decreases rapidly.
Therapeutic CAR-T cells also carry B7H6 on the cell surface. Could NK cells be responsible for the rapid decrease in their number after the start of therapy? Experiments with a humanized mouse model suggest the following: if NK cells were added during leukemia treatment with CAR-T cells, the number of therapeutic cells decreased, while the tumor burden increased.
“The control of T cells by NK has the potential to interfere with various forms of cancer immunotherapy. By specifically intervening in this process, it may be possible to modulate T cell immune responses in the future,” explains Michael Platten. , director of the current study. With the help of CRISPR-Cas genetic scissors, researchers want to protect CAR-T cells from elimination by NK cells in a clinical trial together with the Department of Hematology and Oncology at Heidelberg University Hospital and thus improve the effectiveness of cellular immunotherapy. .