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posted on 2023-03-31, 00:45 authored by Mark J. Bucsek, Guanxi Qiao, Cameron R. MacDonald, Thejaswini Giridharan, Lauren Evans, Brian Niedzwecki, Haichao Liu, Kathleen M. Kokolus, Jason W.-L. Eng, Michelle N. Messmer, Kristopher Attwood, Scott I. Abrams, Bonnie L. Hylander, Elizabeth A. Repasky This data shows that housing mice at 30 degrees Celsius improves the efficacy of anti-PD-1 in both 4T1 and B16-OVA tumor-bearing mice indicating that cool housing temperatures (22 degrees C) impairs the efficacy of anti-PD-1 in murine tumor models.
Funding
Breast Cancer Research
Harry J. Lloyd Charitable Trust
Roswell Park Alliance Foundation
Breast Cancer Coalition
NIH
Roswell Park Cancer Institute
History
ARTICLE 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.
