Dopaminergic Signalling Enhances IL-2 Production and Strengthens Anti-Tumour Response Exerted by Cytotoxic T Lymphocytes in a Melanoma Mouse Model

Dopamine has emerged as an important regulator of immunity. Recent evidence has shown that signalling through low-affinity dopamine receptors exerts anti-inflammatory effects, whilst stimulation of high-affinity dopamine receptors potentiates immunity in different models. However, the dopaminergic regulation of CD8⁺ T-cells in anti-tumour immunity remains poorly explored. Here, we studied the role of dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in the function of CD8⁺ T-cells and its consequences in the anti-tumour immune response. We observed that the deficiency of Drd3 (the gene encoding DRD3) in CD8⁺ T-cells limits their in vivo expansion, leading to an impaired anti-tumour response in a mouse melanoma model. Mechanistic analyses suggest that DRD3 stimulation favours the production of interleukin 2 (IL-2) and the surface expression of CD25, the α-chain IL-2 receptor, which are required for expansion and effector differentiation of CD8⁺ T-cells. Thus, our results provide genetic and pharmacologic evidence indicating that DRD3 favours the production of IL-2 by CD8⁺ T-cells, which is associated with higher expansion and acquisition of effector function of these cells, promoting a more potent anti-tumour response in a melanoma mouse model. These findings contribute to understanding how dopaminergic signalling affects the cellular immune response and represent an opportunity to improve melanoma therapy.