Abstract B026: Exploring the role of neuroblastoma catecholamine production on regulating CD8+ T cell exhaustion

Abstract Neuroblastoma is the most common extracranial solid tumor in children and arises from disruption in the differentiation and proliferation of sympatho-adreno precursor cells. These cells retain the ability to synthesize catecholamines (primarily dopamine, norepinephrine, and epinephrine), which are biomolecules generated by normal tissue and play a crucial role in our stress response. Catecholamines can dampen immune responses by binding to beta-adrenergic receptors on T cells. T cells are critical to antitumor immunity, and activating the beta-adrenergic signaling pathway drives their progressive loss of function, a process known as T cell exhaustion. We hypothesized that the production of catecholamines by neuroblastoma would suppress antitumor immunity by T cells. To investigate the cell-intrinsic role of beta-adrenergic signaling in CD8+ T cell function in neuroblastoma protection, Adrb1–the gene encoding for the beta-1 adrenergic receptor–was disrupted in Cas9 OT-I T cells using lentiviral transduction. After receiving the adoptive transfers of Adrb1-deficient or control T cells, Cas9 mice were subcutaneously implanted with neuroblastoma (9464D-OVA). Mice receiving Adrb1-deficient T cells displayed inferior tumor control, suggesting a previously unrecognized role of this gene in supporting antitumor immunity to neuroblastoma. To complement the genetic approach, we explored the therapeutic potential of atenolol, a commonly prescribed beta-1 selective beta blocker. This experiment yielded similar results, giving a recovery of slightly larger tumor masses of neuroblastoma (9464D-WT) in the control group. Melanoma was used as a tumor control, which like neuroblastoma, originates from neural crest-derived cells. This enabled investigation into the effects of beta-1 blockade in a distinct cancer cell type. Unlike their corresponding neuroblastoma group, the mice receiving the atenolol treatment in the melanoma (B16-OVA) group displayed noticeably superior tumor control. Together these studies suggest that blocking beta-adrenergic signaling may have divergent roles in protection from neuroblastoma and other cancer types. Future experimentation will include exploring the timing and context to selectively augment different differentiation states (i.e. prior to or after exhaustion). Targeting other genes that encode for different beta-adrenergic receptors may also give insight into more effective ways of targeting the beta-adrenergic signaling pathway. Citation Format: Mark Chudnovsky, Elinor Decleene, Naomei Lidman, Daniela Vega-Mendoza, Jose Almeida-Santos, Mingkee Achom, Jared H Rowe. Exploring the role of neuroblastoma catecholamine production on regulating CD8+ T cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B026.