β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells
Klaire Yixin Fjæstad, Astrid Z. Johansen, Hannes Linder, Kevin James Baker, Milou Schattefor, Nadia Kolvig Czajkowski, Marie‐Louise Thorseth, Majken Siersbæk, Annina Kurzay, Maria Perez-Penco, Anne Rahbech, Sara Fresnillo Saló, Lars H. Engelholm, Inge Marie Svane, Mads Hald Andersen, Niels Junker, Lars Grøntved, Per thor Straten, Daniel H. Madsen
Abstract
β-adrenergic signaling has been suggested to promote tumor growth, and β-blockers are being evaluated for repurposing for cancer treatment. Here, we identify a β-adrenergic signaling axis involved in metastasis formation. We show that the β-blocker propranolol has strong anti-metastatic activity in multiple murine models, with this effect being completely dependent on CD4 + T cells and independent of NK or CD8 + T cells. We also observe that CD4 + T cells are required for the anti-tumor effect of propranolol in a syngeneic subcutaneous model of colon cancer. Mechanistically, propranolol induces a Th1-polarized and cytotoxic CD4 + T cell response, which requires MHC class II expression by cancer cells for full efficacy. We also report propanolol-driven systemic changes in the monocyte compartment, and upon depletion of monocytes, propranolol loses its anti-tumor effects. Finally, we show that propranolol treatment synergizes with anti-CTLA-4 therapy to further enhance CD4 + T cell infiltration and control metastasis. Thus, we show that β-adrenergic signaling limits CD4 T cell-mediated anti-tumor immunity, highlighting the potential of repurposing β-blockers for cancer treatment. The interplay between neuronal activity and tumor progression is well-established. Here, the authors demonstrate that blockade of β-adrenergic signaling via administration of propranolol suppresses lung metastasis in multiple mouse tumor models by enhancing the accumulation of cytotoxic CD4 T cells while reducing CCR2+ monocytes, highlighting the re-purposing of β-blockers as a valid therapeutic approach for cancer treatment.