Exploring the role of catecholamine signaling in CD8+ T cell immunity to neuroblastoma

Neuroblastoma (NBL) is the most common extracranial solid tumor in children. NBL tumors arise from the malignant transformation of sympathoadrenal precursor cells in the developing neural crest. The origin of NBL cells leads to their retention of the ability to synthesize catecholamines, which normally regulate our stress response. Recent studies have demonstrated that immune responses are also modulated by catecholamine signaling through beta-adrenergic receptors expressed on T cells. Particularly, catecholamines derived from sympathetic neurons can signal CD8+ T cells via the beta-adrenergic receptor (ADRB1). In tumors this signaling is associated with the progressive loss of CD8+ T cell function, a process known as “exhaustion.” We hypothesized that in catecholamine producing tumors, like NBL, the excessive ADRB1 signaling T cells will suppress antitumor immunity. To investigate the cell-intrinsic role of beta-adrenergic signaling in CD8+ T cell function in protection from NBL we selectively ablated the ADRB1 ( Adrb1 ) gene in murine T cells using an in vivo immune competent NBL model. A syngeneic NBL cell line was engineered to express ovalbumin (OVA) as a surrogate tumor-specific antigen. Cas9-expressing T cell receptor transgenic (TCR) T cells for OVA (Cas9-OT-I) were transduced with Adrb1 -gRNA and adoptively transferred into recipient mice prior to implantation of 9464D-OVA. Surprisingly, we found that Adrb1 -deficient CD8+ T cells had inferior tumor control compared to T cells transduced with non-gene targeting control gRNA. Despite this observation, Adrb1 -deficient CD8+ displayed a competitive advantage in the tumor microenvironment compared to control T cells. This suggests that the loss of ADRB1 is impacting the function of anti-NBL T cells. These findings directly contrasted the robust protection of Adrb1 -deficient CD8+ T cells in a model of melanoma (B16-OVA). Interestingly, we found that pharmacologic treatment of melanoma bearing mice with the selective ADRB1 antagonist atenolol was sufficient to control some tumors and promote animal survival. NBL bearing mice receiving atenolol had no effect on tumor growth or animal survival. Ongoing experiments are addressing how the timing (i.e. pre-activation, post-exhaustion) and context (whole body, T cell-intrinsic, tumor microenvironment) of ADRB1 blockade impacts the function of T cells in NBL. These preclinical studies will support ongoing efforts to target catecholamine signaling to reduce exhaustion and support the function of cellular therapies against NBL.