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Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice
Open accessAbstract
Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of β-adrenergic receptor (βAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (β-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan β-blockers. This retrospective analysis is reinforced by results showing that βAR blockade enhances the control of murine melanoma growth by anti-(α)PD-1 checkpoint blockade. However, this effect was most significant when β-blocker was combined with dual αPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of β2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies.
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“Chronic activation of the sympathetic axis through βAR signaling suppresses cytotoxic T-cell function, whereas β-blockade restores effector activity and improves survival in patients receiving immunotherapy.117”
From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [117]
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ResultSelf-citationLeigh, N. D., Kokolus, K. M., O’Neill, R., Du, W., Eng, J. W. ‐., Qiu, J., Chen, G. L., McCarthy, P. L., Farrar, J. D., Cao, X., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500700 · Cited by 59 · cited 1×
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BackgroundMalignant melanoma—The cradle of anti-neoplastic immunotherapy
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Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
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“This point is reinforced by recent epidemiological data coming from several different cancer settings, supporting the idea that daily use of β-blockers, for indications unrelated to cancer, is associated with improved response to therapy and increased overall survival (44).”
ResultSelf-citationThe β1-adrenergic receptor links sympathetic nerves to T cell exhaustion
Globig, A.-M., Zhao, S., Roginsky, J., Maltez, V. I., Güiza, J., Avina-Ochoa, N., Heeg, M., Hoffmann, F. A., Chaudhary, O., Wang, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06568-6 · Cited by 331
Metadata
- Authors
- Kokolus, K. M., Zhang, Y., Sivik, J. M., Schmeck, C., Zhu, J., Repasky, E. A., Drabick, J. J., & Schell, T. D.
- Affiliations
- Pennsylvania State University (US)
- Penn State Milton S. Hershey Medical Center (US)
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Schell, Todd. D.
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-12-21
- Volume
- 7
- Issue
- 3
- Pages
- e1405205
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5790362
- OpenAlex
- W2768592202
- Cited by
- 200
- References
- 51
- Citations by year
- 2026: 30 · 2025: 23 · 2024: 17 · 2023: 31 · 2022: 23 · 2021: 28 · 2020: 22 · 2019: 21 · 2018: 5
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pennsylvania Department of Health (PDH) (SAP #4100072562)
- HHS | National Institutes of Health (NIH) (CA060395)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- beta-blockers, metastatic melanoma, immunotherapy, beta-adrenergic signaling, anti-PD-1 therapy, interleukin-2, beta2-adrenergic receptor, overall survival, combination therapy, murine melanoma model
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