β-Adrenergic Signaling through ADRB1 Promotes CD8⁺ T-cell Exhaustion

Exhausted CD8⁺ T cells can be targeted by immune checkpoint blockade (ICB), but responses are limited to a subset of patients, and a further understanding of mechanisms governing T-cell exhaustion may expand the efficacy of ICB. It is also unknown how stress responses in tissues resulting from chronic infection or cancer may contribute to T-cell exhaustion and whether activation of the sympathetic nervous system by acute or chronic stress can directly influence T-cell functions. Globig and colleagues identified genes upregulated during CD8⁺ T-cell differentiation from progenitor to exhausted states in a mouse model of chronic infection with lymphocytic choriomeningitis virus (LCMV) and found that the β₁-adrenergic receptor Adrb1 was specifically induced in terminally exhausted T cells. Chronic infection also led to increased systemic noradrenaline and induction of downstream targets of ADRB1 signaling, including cAMP and the cAMP-responsive gene Crem. Exhausted T cells colocalized with sympathetic nerves in LCMV-infected mice, as well as in a murine pancreatic cancer model and in human non–small cell lung cancer tissue, suggesting that T cells respond to stress signals in tissues during both infection and malignancy. Overexpression of Adrb1 in CD8⁺ T cells was sufficient to impair proliferation and cytokine output in vitro and in vivo. Additionally, Adrb1 deletion specifically in CD8⁺ T cells in vivo inhibited differentiation to terminally exhausted states, impaired migration toward sympathetic nerves, and enhanced response to ICB. Notably, pharmacologic blockade of ADRB1 in chronic infection and melanoma models induced CD8⁺ T-cell activation and proliferation, and combination therapy of ICB and β-blockade resulted in a synergistic decrease in melanoma tumor burden. Finally, in a mouse model of pancreatic ductal adenocarcinoma, a tumor type refractory to ICB, combination treatment with a β-blocker and ICB induced CD8⁺ T-cell infiltration and activation and led to a T cell–dependent reduction in tumor growth. In summary, this study identified ADRB1 as an immune checkpoint molecule that can be targeted to restore CD8⁺ T-cell activity and enhance the efficacy of ICB.

Globig AM, Zhao S, Roginsky J, Maltez VI, Guiza J, Avina-Ochoa N, et al. The β₁-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 2023 Sep 20 [Epub ahead of print].

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