Catecholamines drives cytokine release syndrome (CRS) in response to bacteria and antitumor agents.

  • Major finding: Catecholamines drives cytokine release syndrome (CRS) in response to bacteria and antitumor agents.

  • Mechanism: Myeloid cell secretion of catecholamines induces cytokines that promote inflammatory injury.

  • Impact: Inhibition of catecholamine synthesis reduces CRS without diminishing therapeutic responses.

Treatment with various antitumor immunotherapies, including oncolytic bacteria, T cell–targeting antibodies, and chimeric antigen receptor (CAR) T cells, often results in a systemic and damaging hyperactivation of immune responses known as cytokine release syndrome (CRS), which significantly limits the efficacy of these agents and can be life-threatening. Staedtke, Bai, and colleagues found that the severe and lethal cytokine release induced by the oncolytic bacteria Clostridium novyi-NT in tumor-bearing mice was mitigated by the anti-inflammatory protein atrial natriuretic peptide (ANP). Bacterial expression or systemic delivery of ANP reduced myeloid-derived cytokines and inflammatory tissue damage while maintaining the antitumor efficacy of C. novyi-NT. Mechanistically, ANP inhibited macrophage-derived secretion of catecholamines, which are known to signal via adrenergic receptors to induce cytokine production in response to inflammatory stimuli. Consistent with these findings, direct inhibition of catecholamine synthesis with α-methyltyrosine (MTR), myeloid-specific deletion of the gene encoding tyrosine hydroxylase, or blockade of α-adrenergic receptors suppressed catecholamine and cytokine release by macrophages both in vitro and in mice. Similar to the effects of C. novyi-NT infection, treatment with a T cell–targeting anti-CD3 antibody or CD19-directed CAR T cells also resulted in a systemic increase in catecholamines and proinflammatory cytokines, whereas pretreatment with MTR or ANP eliminated amplification of the catecholamine-driven inflammatory response and protected against CRS-associated mortality. Importantly, pretreatment with MTR or ANP did not impair CAR T-cell expansion or tumor clearance in mouse models of Burkitt lymphoma and B-cell acute lymphoblastic leukemia. These results identify a self-amplifying autocrine catecholamine loop in myeloid cells as an essential mediator of CRS in response to bacterial infection and T cell–targeting antitumor agents and suggest that pharmacologic inhibition of catecholamine synthesis may prevent CRS toxicity in patients receiving immunotherapies.

Staedtke V, Bai R-Y, Kim K, Darvas M, Davila ML, Riggins GJ, et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 2018;564:273–7.

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