Adrenergic receptors regulate T cell differentiation in viral infection and cancer

Abstract

Abstract CD8 +T cells are critical components of the immune reaction against viral infections and cancer and have the potential to eliminate infected or malignant cells. However, when the antigen persists, CD8 +T cells enter an exhausted state. Chronic disease can lead to increased systemic noradrenaline (NA) levels, but it is currently still unclear how NA impacts the differentiation and function of exhausted CD8 +T cells. We here set out to characterize the effects of β adrenergic signaling on CD8 +T cells in chronic viral infection with LCMV-clone 13 and in murine cancer models. We observed that chronically infected mice had elevated systemic NA levels and CD8 +T cells expressed higher levels of the β-1 adrenergic NA receptor, Adrb1. NA impaired T cell receptor signaling of ADRB1-expressing CD8 +T cells, and reduced T cell proliferation and function. Conversely, genetic ablation of ADRB1 prevented terminal CD8 +T cell differentiation in chronic viral infection and ADRB1-blockade enhanced T cell functionality in combination with immune checkpoint blockade (ICB) in an ICB-sensitive melanoma model. Expanding these observations to an ICB-resistant model of pancreatic cancer, we found that pharmacological blockade of adrenergic receptors synergized with ICB to genetically reprogram CD8 +T cells towards a tissue resident memory T cell-like state and improved T cell functionality, resulting in decreased tumor size. In summary, our data suggest that β adrenergic receptors represent a novel immune checkpoint that modulates CD8 +T cell differentiation and function in the context of chronic antigen exposure and that targeting adrenergic receptors may synergize with ICB in cancer patients. AMG was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, GL 991/1-1). SZ was supported by K00CA222741. This work was supported by grants from the NIH 5 R01 CA240909 (SMK) and 5 R01 CA216101 (SMK).