New T-cell control mechanism may hinder cancer immunotherapy

Natural killer (NK) cells, integral components of our immune system, have been found to control activated T cells that display a specific marker protein on their surface. This regulation is presumed to prevent harmful immune reactions. However, recent research has shown that NK cells can inadvertently hinder the effectiveness of cancer therapies that use immune checkpoint inhibitors (ICI) and may also contribute to the swift reduction of therapeutic CAR-T cells. Adjusting this mechanism might enhance the success of these cancer immunotherapies.

The immune system’s T cells are crucial for defending against viral infections and cancerous cells. Yet, they can also mistakenly attack the body's own healthy tissues, leading to dangerous autoimmune reactions. Therefore, it is vital to tightly regulate T cell activity. This complex regulation involves numerous molecules and signals, and it has recently been discovered that NK cells, which are part of the body's innate immune response, also play a role in this process. NK cells are known for their ability to quickly identify and eliminate infected or cancerous cells.

Michael Platten, Head of Department at the German Cancer Research Center (DKFZ) and Director of the Neurological University Clinic Mannheim, points out that NK cells can kill activated T cells, thereby limiting their proliferation. However, the specific feature that identifies T cells as targets for NK cells was previously unknown. Platten's team has now identified the protein B7H6 on the surface of activated T cells as a recognition molecule for NK cell attacks. Activated T cells from patients with autoimmune diseases, cancer, or viral infections show high levels of B7H6. Laboratory experiments revealed that NK cells recognize and attack these T cells based on their B7H6 expression. Conversely, T cells lacking the B7H6 gene, removed via CRISPR-Cas technology, were shielded from NK cell attacks.

Michael Kilian, the first author of the study, explains that T cells themselves trigger their identification as targets for NK cells, which helps to control excessive T cell activation and expansion, thereby preventing destructive immune responses.

The study also explores how NK cells can neutralize the effects of immune checkpoint inhibitors (ICIs). ICIs are a class of cancer therapies that target specific inhibitory checkpoint molecules to activate the immune system against tumors. The researchers investigated whether the B7H6-mediated elimination of tumor-reactive T cells could undermine the efficacy of ICI cancer immunotherapy. Their analysis of tissue samples from esophageal cancer patients undergoing ICI therapy revealed that those who did not respond well to the treatment had higher numbers of NK cells in their tumor tissue and experienced shorter progression-free survival times.

Cellular immunotherapies, such as CAR-T cell therapy, are increasingly important in cancer treatment. CAR-T cells are customized to target cancer cells. However, these therapeutic cells often decline rapidly in patients' bodies, limiting the success of the therapy. CAR-T cells also express B7H6 on their surface, raising the question of whether NK cells are responsible for their rapid decline after therapy initiation. Experiments with a humanized mouse model indicated that the presence of NK cells during CAR-T cell treatment of leukemia led to a decrease in therapeutic cells and an increase in tumor load.

Michael Platten emphasizes that NK cell control over T cells can potentially interfere with various cancer immunotherapies. By intervening in this process, it might be possible to modulate T cell immune responses more effectively. The research team aims to protect CAR-T cells from NK cell elimination using CRISPR-Cas technology in a clinical trial with the Department of Hematology and Oncology at Heidelberg University Hospital, thereby improving the efficacy of cellular immunotherapy.