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Cancer Res. 2017 Oct 15;77(20):5639-5651. doi: 10.1158/0008-5472.CAN-17-0546. Epub 2017 Aug 17.

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy.

Author information

1
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
2
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
3
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. elizabeth.repasky@roswellpark.org.

Abstract

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639-51. ©2017 AACR.

PMID:
28819022
PMCID:
PMC5645237
DOI:
10.1158/0008-5472.CAN-17-0546
[Indexed for MEDLINE]
Free PMC Article

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