Abstract B036: Neurotransmitter Modulation in Tumor-Infiltrating Immune Cells: Targeting Dopamine Beta-Hydroxylase Enhances Immune Checkpoint Blockade Efficacy in Melanoma

作者：Didem Ağaç Çobanoğlu, Murat Can Çobanoğlu, Mahshid Arabi, James P. Allison · 发表于：Cancer Immunology Research · 年份：2025 · DOI：10.1158/2326-6074.io2025-b036 · 被引用次数：1 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Adenosine and Purinergic Signaling、Tryptophan and brain disorders

Abstract Immune checkpoint blockade (ICB) therapies work by disrupting inhibitory signals that dampen T-cell activation, thus rejuvenating tumor-specific T cells. While ICB has shown durable responses in some patients, a significant number do not benefit, underscoring the need to explore additional inhibitory mechanisms. The modulation of immune responses by neurotransmitters (NTs) has been studied in various disease settings in the context of multiple receptors, including adrenergic receptors, dopaminergic receptors, and cholinergic receptors. NT receptors are highly expressed on immune cells, and the signaling through these receptors has been reported to be immunosuppressive. Although the neural control of immunity has been studied elsewhere, its role in the tumor setting remains underexplored. We showed that tumor-infiltrating lymphocytes (TILs) in melanoma express diverse NT receptors. We have identified dopamine and norepinephrine, among other NTs, in the murine melanoma TME through mass spectrometry. Furthermore, we observed the expression of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine to norepinephrine, in human and mouse TILs. TILs can convert dopamine to norepinephrine ex vivo, demonstrating the functional activity of DBH. T cells expressing DBH have elevated levels of exhaustion markers like CTLA-4, PD-1, and LAG-3, as well as TOX, a transcription factor associated with exhausted T cells. We hypothesized that DBH-expressing cells contribute additi...