4.8 Article

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

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CANCER RESEARCH
卷 77, 期 20, 页码 5639-5651

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0546

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  1. Peter T. Rowley Breast Cancer Research Grant [C028252]
  2. Harry J. Lloyd Charitable Trust
  3. Roswell Park Alliance Foundation
  4. Breast Cancer Coalition of Rochester, NY
  5. NIH [5T32CA085183, 1-R01CA140622]
  6. Roswell Park Cancer Institute's Comprehensive Cancer Center Support Grant [CA016056]

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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 beta(2)-adrenergic receptor (beta-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (beta-blockers), and genetic (beta(2)-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing beta-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 (IFN gamma(+) 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 beta-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available beta-blockers in patients to improve responses to immunotherapy. (C) 2017 AACR.

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