Neurotransmitter modulation of anti-tumor responses: new avenues for enhancing immunotherapy 2602

Abstract Description Immune checkpoint blockade (ICB) therapies work by disrupting inhibitory signals that dampen T-cell activation, rejuvenating tumor-specific T cells. While ICB shows durable responses in some patients, many do not benefit, highlighting the need to explore other inhibitory mechanisms. Neurotransmitter (NT) signaling, known to be immunosuppressive in various disease models, is underexplored in the tumor microenvironment (TME). We found that tumor-infiltrating lymphocytes (TILs) in melanoma express diverse NT receptors. Using mass spectrometry, we detected dopamine and norepinephrine in the murine melanoma TME. Additionally, we observed dopamine beta-hydroxylase (DBH)—an enzyme converting dopamine to norepinephrine—in both human and mouse TILs, which can convert dopamine to norepinephrine ex vivo, indicating DBH activity. T cells expressing DBH also showed high levels of exhaustion markers such as CTLA-4, PD-1, and LAG-3. Our results show that adrenergic receptor antagonists or DBH inhibitors enhance anti-tumor responses when combined with ICB. We further investigated DBH’s role using DBH conditional knockout and reporter mice. This research highlights a novel, pharmacologically targetable pathway involving NT production by immune cells. The presence of DBH-expressing immune cells in various tumors suggests broader implications, with NT-modulating drugs showing promise for advancing melanoma and other cancer treatments. Funding Sources DAC is an MDACC Odyssey fellow. MCC is supported by the Lyda Hill Department of Bioinformatics Startup Funds. DAC and MCC were awarded Melanoma Research Foundation Breakthrough Consortium-Bristol Myers Squibb (MRFBC-BMS) Young Investigator Translational Immuno-Oncology Team Science Award. This work was also supported by Grant R1203 from CPRIT (JPA). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)