| First Author | Bucsek MJ | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 20 | Pages | 5639-5651 |
| PubMed ID | 28819022 | Mgi Jnum | J:245651 |
| Mgi Id | MGI:5917579 | Doi | 10.1158/0008-5472.CAN-17-0546 |
| Citation | Bucsek MJ, et al. (2017) beta-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res 77(20):5639-5651 |
| abstractText | 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 beta2-adrenergic receptor (beta-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (beta-blockers), and genetic (beta2-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 (IFNgamma+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. Cancer Res; 77(20); 5639-51. (c)2017 AACR. |
