β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy
| Autor: | Cameron R. MacDonald, Scott I. Abrams, Thejaswini Giridharan, Bonnie L. Hylander, Mark J. Bucsek, Jason W.-L. Eng, Haichao Liu, Guanxi Qiao, Kathleen M. Kokolus, Michelle N. Messmer, Kristopher Attwood, Brian Niedzwecki, Lauren Evans, Elizabeth A. Repasky |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Tumor microenvironment Regulatory T cell Effector medicine.medical_treatment T cell Immunotherapy Biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Immune system Oncology 030220 oncology & carcinogenesis Immunology medicine Cancer research Cytotoxic T cell CD8 |
| Zdroj: | Cancer Research. 77:5639-5651 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-0546 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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