Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome

Verena Staedtke (), Ren-Yuan Bai (), Kibem Kim, Martin Darvas, Marco L. Davila, Gregory J. Riggins, Paul B. Rothman, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein () and Shibin Zhou ()
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Verena Staedtke: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center
Ren-Yuan Bai: Johns Hopkins University School of Medicine
Kibem Kim: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center
Martin Darvas: University of Washington
Marco L. Davila: H. Lee Moffitt Cancer Center and Research Institute
Gregory J. Riggins: Johns Hopkins University School of Medicine
Paul B. Rothman: Johns Hopkins University School of Medicine
Nickolas Papadopoulos: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center
Kenneth W. Kinzler: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center
Bert Vogelstein: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center
Shibin Zhou: Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center

Nature, 2018, vol. 564, issue 7735, 273-277

Abstract: Abstract Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1–5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.

Keywords: Cytokine Release Syndrome (CRS); Atrial Natriuretic Peptide; Spore Injection; Epinephrine Detection; Luminal Entry (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0774-y

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