T cells activated with a specific surface marker protein are regulated by natural killer (NK) cells, another component of the immune system. This regulatory mechanism potentially prevents harmful immune reactions. Scientists from the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim (UMM) have revealed that NK cells may hinder the effectiveness of cancer treatments involving immune checkpoint inhibitors (ICI) and contribute to the rapid decline of therapeutic CAR-T cells. Alterations in this mechanism could enhance the efficacy of cellular cancer immunotherapies. The findings are published in the journal Science Immunology.
T cells play a vital role in defending against viral infections and cancerous cells, yet they can also attack healthy tissues in autoimmune responses. Therefore, strict control over T cell activity is necessary. While numerous molecules and messengers are involved in regulating T cell activity, recent research has uncovered the role of another group of immune cells in this control process. NK cells, which are part of the innate immune system, detect and eliminate infected or malignant cells rapidly.
“NK cells have been found to eliminate activated T cells, thus limiting their proliferation,” says Michael Platten, Department Head at DKFZ and Director of the Neurological University Clinic Mannheim. However, the specific feature identifying T cells as targets for NK cells was previously unknown.
In a recent study, Platten’s team identified the protein B7H6 as a recognition molecule for NK cell attacks on activated T cells. They found that activated T cells from patients with autoimmune diseases, cancer, or viral infections exhibit significant B7H6 expression on their surface. Co-culture experiments revealed that NK cells recognize activated T cells through their B7H6 expression. Conversely, T cells with disrupted B7H6 genes were protected from NK cell attacks.
“The elimination of T cells by NK cells is driven by an intrinsic mechanism of the T cells themselves. Activated T cells temporarily mark themselves as targets for NK-induced cell lysis,” explains Michael Kilian, the study’s first author. This mechanism serves to limit excessive T cell activation and expansion, thereby controlling destructive immune responses.
B7H6 identified as a new immune checkpoint molecule on T cells “B7H6 can now be classified as another inhibitory immune checkpoint on T cells,” states Platten. Immune checkpoint inhibitor (ICI) therapies, widely used in cancer treatment, target specific inhibitory checkpoint molecules to activate the immune system against tumors. However, the researchers found that the B7H6-mediated elimination of tumor-reactive T cells might counteract the efficacy of ICI cancer immunotherapy. Tissue samples from patients with esophageal cancer receiving ICI therapy revealed that non-responders had higher NK cell levels in tumor tissue and shorter progression-free survival times.
NK cells impede cellular immunotherapy effectiveness Cellular immunotherapies, such as CAR-T cell therapy, are increasingly vital in cancer treatment. CAR-T cells, equipped with customized receptors against cancer, are used to treat certain blood cancers. However, the success of this therapy is often limited by the rapid decline in therapeutic cell numbers in the patient’s body.
Experimental studies using a humanized mouse model suggested that the addition of NK cells during CAR-T cell treatment of leukemia led to a decrease in therapeutic cell numbers and an increase in tumor burden. This suggests that NK cells may be responsible for the rapid decline in CAR-T cell numbers post-therapy.
“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,” Platten explains. The researchers aim to protect CAR-T cells from NK cell elimination in a clinical trial using CRISPR-Cas gene editing, in collaboration with the Department of Hematology and Oncology at Heidelberg University Hospital, to improve the efficacy of cellular immunotherapy.
