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

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 additional inhibitory signals in the TME. We showed that adrenergic receptor antagonists or DBH inhibitors enhanced anti-tumor responses when combined with ICB. Detailed kinetic analysis of spleen, tumor draining lymph nodes and tumors showed that DBH expression increases in time in tumor bearing animals. Furthermore, we generated and studied DBH conditional knockout mice for various immune cells and DBH reporter mice to study the role of this gene in depth. This research highlights a novel, pharmacologically targetable pathway involving NT production by immune cells. More importantly, this pathway can be synergized with ICB to improve efficacy. Additionally, we computationally observed DBH-expressing immune cells in various tumors, suggesting broader implications. Given the availability of FDA-approved NT-modulating drugs, our work holds promise for advancing the standard of care in melanoma and potentially other cancers. Citation Format: Didem Cobanoglu, Murat Can Cobanoglu, Mahshid Arabi, James P Allison. Neurotransmitter Modulation in Tumor-Infiltrating Immune Cells: Targeting Dopamine Beta-Hydroxylase Enhances Immune Checkpoint Blockade Efficacy in Melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B036.