The eradication of cancer in a patient can be a daunting problem especially when the cancer is widespread and not responsive to chemotherapy. There are multiple reasons for the inability to eradicate a patient’s cancer.
- The inability to remove the disease by surgery
- The cancer is not sensitive to chemotherapy
- The cancer is not contained by the patient’s own immune system
Immune surveillance is a major hypothesis underlying the ability of the immune system to control or eradicate tumors at an early stage. But, we still do not a full picture of how tumors escape immune control or how our immune system can best be harnessed to control both early cancers as well as advanced, widespread disease. Understanding events which actively suppress the on-going anti-tumor immune network have risen to the top of research priorities in the field of tumor immunology.
Roswell Park researchers are working on strategies to modulate the immune response to cancer treatment and control by overcoming immunosuppression. Recently, Dr. Hemn Mohammadpour, a post-doctoral fellow in the laboratories of Drs. Elizabeth Repasky and Philip McCarthy, described in elegant detail how stress—specifically, the adrenergic stress which involves the sympathetic nervous system—can enhance immunosuppression (Mohammadpour et al JCI 2019).
The adrenergic nervous system controls multiple organ systems including the heart, muscle, nerve tissue and the gastrointestinal tract. Stress is in part controlled by the autonomic nervous system. Two of the major mediators of this system are epinephrine and norepinephrine. These neurotransmitters are known as catecholamines. The body’s receptors for these transmitters are the beta-adrenergic receptors. The “flight or fight” response is a well understood part of the autonomic nervous system and the body’s response to stress.
However, it is not generally appreciated that a variety of chronic forms of stress, such as anxiety, fear or depression, also activate the signaling through adrenergic receptors. The investigators at Roswell Park have been concerned about how increased stress experienced in cancer patients might be influencing their responses to cancer therapies, and especially, how chronic stress may contribute to immunosuppression.
Prior work had identified that immunotherapy does not work as well in mice experiencing mild chronic stress (Bucsek et al Cancer Research 2017) but could be improved by treatment with a common, widely available drug known as a beta-blocker. This has led to the development of Roswell Park clinical trials to use beta blockers to enhance the effect of immunotherapy. But now, a major underlying mechanism which helps to explain this effect has been identified in the Mohammadpour et al publication. Here the team has made important observations in how catecholamines influence an immune modulatory cell called myeloid-derived suppressor cells (MDSCs).
In pre-clinical tumor models, chronic stress was shown to result in increased tumor growth. This increased tumor growth was associated with an increase in MDSCs. Excitingly, this increase in tumor growth and increased MDSCs could also be blocked by beta-blockers which block the catecholamine interaction with beta adrenergic receptors on MDSCs and other immune cells. This manuscript was featured in the Commentary of the journal, Nature Immunology. We will provide a more detailed update in a future newsletter.
Mohammadpour H, MacDonald CR, Qiao G, Chen M, Dong B, Hylander BL, McCarthy PL, Abrams SI, Repasky EA. ?2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 2019 Dec 2;129(12):5537-5552. doi: 10.1172/JCI129502. https://www.ncbi.nlm.nih.gov/pubmed/31566578
Commentary on Mohammadpour H et al. Dempsey LA. ?2-AR signaling in MDSCs. Nat Immunol. 2020 Jan;21(1):8. doi: 10.1038/s41590-019-0574-z. https://www.ncbi.nlm.nih.gov/pubmed/31848490
Bucsek MJ, Qiao G, MacDonald CR, Giridharan T, Evans L, Niedzwecki B, Liu H, Kokolus KM, Eng JW, Messmer MN, Attwood K, Abrams SI, Hylander BL, Repasky EA. ?-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res. 2017 Oct 15;77(20):5639-5651. doi: 10.1158/0008-5472.CAN-17-0546. Epub 2017 Aug 17. PMID: 28819022. https://www.ncbi.nlm.nih.gov/pubmed/28819022