Immune checkpoint inhibitors: Interaction between PD-1 and PD-L1  blocked by therapeutic antibodies
Credit: selvanegra/Getty Images

A mechanism by which natural killer (NK) cells impede immune checkpoint inhibitors (ICIs) in cancer treatment has been uncovered by researchers from the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim (UMM). The team found that the immunoglobulin superfamily ligand B7H6 promotes cytolysis of activated T cells by NK cells. Better understanding this mechanism, and designing interventions against it, could improve the efficacy of cancer immunotherapies.

The report was published in Science Immunology and Michael Kilian, PhD, a postdoctoral researcher at the DKFZ, is first author.

“We show that activated T cells express the NKP30 ligand B7H6 and show that T cells are lysed by NK cells in a NKp30/B7H6 dependent manner. Additionally, we show that in pathophysiological settings like autoimmunity and viral infections, cytotoxic T cells express B7H6,” Kilian told Inside Precision Medicine.

T cells are the main players in the immune system’s defense against viral infections and tumor cells. Recently researchers discovered that natural killer cells (NK cells) also contribute to the control of T-cell activity. 

“Studies have shown that NK cells can also kill activated T cells and thus limit their proliferation,” says Michael Platten, MD, head of department at the DKFZ, director of the Neurological University Clinic Mannheim, and head of the current study. “However, until now we did not know which feature characterizes T cells as a target for the NK cell.”

In this research, activated T cells from the blood of patients with autoimmune diseases, cancer, or viral infections exposed large amounts of B7H6 on their surface. Co-culture experiments showed that NK cells recognize the activated T cells by their B7H6 expression. In contrast, T cells whose B7H6 gene was muted with CRISPR-Cas were protected from the lethal attack of the NK cells.

“The elimination of T cells by NK cells is triggered by an intrinsic mechanism of the T cells. The activated T cells temporarily identify themselves as targets for NK-induced cell lysis,” Kilian adds. “This may limit excessive activation and expansion of T cells as a control mechanism to curb destructive immune responses.”

“We now know a number of so-called checkpoint molecules that reduce or enhance the activation of T cells and thus modulate the course of immune reactions. B7H6 can now be classified as a further inhibitory immune checkpoint on T cells,” explains Platten.

Could the B7H6-mediated elimination of tumor-reactive T cells possibly counteract the effect of ICI cancer immunotherapy? The researchers tested this using tissue samples from patients with esophageal cancer 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 actually had a shorter progression-free survival time.

Cellular immunotherapies are becoming increasingly important in cancer medicine. For example, some forms of blood cancer are now often treated with so-called CAR-T cells, which also carry B7H6 on the cell surface. Could NK cells be responsible for the rapid decline in their numbers after the start of therapy? Experiments with a humanized mouse model suggest that if NK cells were added during CAR-T cell treatment of leukemia, the number of therapeutic cells decreased, while the tumor load increased.

“NK control of T cells 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 Platten. With the help of the CRISPR-Cas gene scissors, the researchers now 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.

Also of Interest