Salk Institute scientists discovered a link between killer T cell exhaustion and the “fight-or-flight” response in various cancers. They found that beta-blockers, already used in humans, can enhance killer T cells’ tumor-fighting abilities. Published in Nature on September 20, 2023, this study unveils a new connection between stress response and cancer immunity, suggesting beta-blockers could boost cancer treatment when combined with immunotherapies.

“There is no question immunotherapy has revolutionized cancer patient treatment – but there are many patients for whom it’s ineffective,” says Professor Susan Kaech, senior author and director of Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis. “Finding that our nervous system can suppress the function of cancer-destroying immune cells opens up entirely new ways to think about how to rejuvenate T cells in tumors.”

Researchers studied how sympathetic nerves release noradrenaline, a stress hormone, affecting killer T cells, revealing a lack of understanding of the sympathetic nervous system's impact on immune responses.

Researchers discovered noradrenaline binds to T cells via ADRB1 receptor, and blocking ADRB1 with beta-blockers improves T cell function, showing promise in cancer treatment, but impairs cancer-fighting abilities.

“The innervation of tumors is an understudied area of tumor immunology. Our study has now uncovered that nerves contribute to the process of T cell exhaustion in tumors, where T cells become worn out and less powerful in their fight against the tumor over time,” says first author Anna-Maria Globig, a postdoctoral researcher in Kaech’s lab. “If we can unravel the details of how nerves suppress the body’s immune response to cancer and why the exhausted T cells move towards the nerves, we can begin to target this process therapeutically.”

According to Kaech, the researchers hope to expand their understanding of the exhausted killer T cell environment to learn more about why stress makes us sicker.

“We were able to find a new pathway that we can target with beta-blockers to create more resilient killer T cells that resist exhaustion and fight cancer better,” says Globig.

The team plans to apply their beta-blocker-based cancer treatment to lung cancer patients, collaborating with clinicians. They aim to expand their research with more human cancer tissue samples for stronger evidence of beta-blockers’ effectiveness.

Other authors involved in this study are from various institutions, and the research received support from multiple sources, including the German Research Foundation, NOMIS Foundation, and National Institutes of Health.