A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response

Abstract

Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and β-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies.

Fig. 1

Physical dangers, such as predators or changes in the surrounding environment, induce signaling from the cortex or the hypothalamus to nuclei located in the medulla. These nuclei project axons onto cell bodies located in the intermediolateral column of the T1 and L3 spinal cord. From there, cells synapse with postsynaptic ganglia located in the sympathetic trunk or in splanchnic ganglia throughout the body. In addition, presynaptic neurons innervate cells of the adrenal medulla to induce hormone production. Therefore, signaling from the sympathetic nervous system can affect tissues and cells located throughout the body

Fig. 2

Stress induces production of several neurotransmitters and hormones which can enter the tumor microenvironment through vasculature, innervation, or even locally by infiltrating immune cells. Activation of the adrenergic receptors on immune cells results in the production of immunosuppressive molecules such as CTLA-4, arginase, and iNOS. Simultaneously, the catecholamines can also inhibit the production of important activation cytokines such as IFN-γ, IL-2, and IL-12. In addition, increased levels of stress hormones in the tumor microenvironment can also increase the levels of IDO, PD-L1, and COX-2 expressed by the tumor, which facilitates immune dysfunction and increases expression of pro-survival and pro-metastatic molecules