Beta-Blockers and Immunotherapy: A Promising Combination for Improved Cancer Treatment Outcomes

Vikas P. Sukhatme, MD, ScD

Introduction

In recent years, a fascinating connection has emerged between stress hormones, cancer progression, and immune function. Researchers have discovered that stress-related hormones may impair the effectiveness of cancer immunotherapy treatments by suppressing immune responses. This has led to an intriguing hypothesis: could medications that block these stress pathways, such as beta-blockers, enhance the efficacy of immunotherapy?

What the Research Shows

Several studies involving hundreds of patients across different cancer types have found that patients who happened to be taking beta-blockers while receiving immunotherapy showed better treatment outcomes compared to those on immunotherapy alone.

  • In non-small cell lung cancer patients treated with immune checkpoint inhibitors, Oh and colleagues (2021) found that patients who were taking beta-blockers while receiving immune checkpoint inhibitors had a 42% reduction in the risk of disease progression compared to those not taking beta-blockers.
  • In melanoma patients, Gandhi and colleagues (2021) conducted a phase I clinical trial combining the beta blocker propranolol with pembrolizumab and observed promising response rates of 78% in a small cohort of patients with metastatic melanoma. In retrospective analyses, Kokolus and colleagues (2018) found that melanoma patients taking beta-blockers while receiving immunotherapy had improved overall survival compared to those on immunotherapy alone.
  • In preclinical studies, Mohammadpour and colleagues (2019) demonstrated that beta-blocker therapy reduced the numbers of immunosuppressive cells and enhanced the anti-tumor immune response in mouse models of cancer.
  • In a comprehensive review, Carnet Le Provost and colleagues (2023) examined the growing body of evidence supporting the use of beta-blockers in cancer therapy, highlighting their potential to enhance immunosurveillance and improve responses to immunotherapy across multiple tumor types.
  • In another review, Massalee and Cao (2024) discussed how beta-blockers can reprogram the tumor microenvironment to favor anti-tumor immune responses, particularly when combined with immune checkpoint inhibitors.

Why Beta-Blockers May Help: The Science Behind the Effect

Our bodies operate on a delicate balance of hormones and signaling pathways. When we experience stress, our sympathetic nervous system triggers the release of stress hormones like epinephrine and norepinephrine (also known as adrenaline and noradrenaline). These hormones bind to adrenergic receptors, including beta-adrenergic receptors, on various cells throughout the body.

Research by Bucsek and colleagues (2017) has shown that stress hormones can significantly suppress immune function by:

  • Reducing the activity and proliferation of CD8+ T cells (the "killer" immune cells that attack cancer)
  • Increasing the number and function of immunosuppressive cells like myeloid-derived suppressor cells (MDSCs)
  • Altering cytokine profiles in ways that favor tumor growth and immune evasion

Beta-blockers work by blocking these adrenergic receptors, potentially preventing the negative effects of stress hormones on immune function. This may create a more favorable environment for immunotherapy drugs to activate the immune system against cancer cells.

Clinical Implications

The findings from these studies suggest that combining beta-blockers with immunotherapy could be a simple but effective strategy to improve cancer treatment outcomes. Beta-blockers are already widely used, inexpensive medications with well-understood safety profiles, primarily prescribed for cardiovascular conditions like hypertension.

What This Means for Patients

These findings open up intriguing possibilities for enhancing the effectiveness of immunotherapy. For patients already taking beta-blockers for cardiovascular conditions, this research suggests they may have an added advantage when receiving immunotherapy.

For those not currently on beta-blockers, the research is still evolving, and several clinical trials are currently investigating the deliberate addition of beta-blockers to immunotherapy regimens. It's important to note that beta-blockers should only be taken under medical supervision, as they may not be appropriate for all patients due to potential contraindications or side effects.

Future Directions

Ongoing and planned clinical trials are now specifically examining the combination of beta-blockers with immunotherapy across multiple cancer types. These studies will help determine:

  • The optimal timing and dosing of beta-blockers
  • Which specific beta-blockers work best in combination with immunotherapy (so far, the data seems to support so-called non-selective beta-blockers such as propranolol)
  • Which patients are most likely to benefit from this approach

As this research progresses, the combination of beta-blockers and immunotherapy may become an established treatment strategy, potentially improving outcomes for patients with various types of cancer.

References

  1. Bucsek MJ, Qiao G, MacDonald CR, Giridharan T, Evans L, Niedzwecki B, et al. Beta-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res. 2017;77:5639–5651.
  2. Carnet Le Provost K, Kepp O, Kroemer G, Bezu L. Trial watch: beta-blockers in cancer therapy. Oncoimmunology. 2023;12:2284486.
  3. Gandhi S, Pandey MR, Attwood K, Ji W, Witkiewicz AK, Knudsen ES, et al. Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clin Cancer Res. 2021;27:87-95.
  4. Kokolus KM, Zhang Y, Sivik JM, Schmeck C, Zhu J, Repasky EA, et al. Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice. Oncoimmunology. 2018;7.
  5. Massalee R, Cao X. Repurposing beta-blockers for combinatory cancer treatment: effects on conventional and immune therapies. Front Pharmacol. 2024;14:1325050.
  6. Mohammadpour H, MacDonald CR, Qiao G, Chen M, Dong B, Hylander BL, et al. β2-adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 2019;129:5537-5552.
  7. Oh MS, Guzner A, Wainwright DA, Mohindra NA, Chae YK, Behdad A, et al. The impact of beta blockers on survival outcomes in non-small cell lung cancer patients treated with immune checkpoint inhibitors. Clin Lung Cancer. 2021;22.