Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

Abstract

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

Manipulation of Ambient Housing Temperature To Study the Impact of Chronic Stress on Immunity and Cancer in Mice

“…To our knowledge, our group first reported that mouse models of cancer and antitumor immunity (39)(40)(41), immune responses in graft versus host disease (42), dendritic cell biology (43), and radiosensitivity of hematopoietic stem cells (44) are each significantly influenced by room temperature. These are representative of a growing number of papers reporting how choice of housing temperature impacts experimental outcomes and reproducibility in several mouse models of disease and we have recently reviewed this topic (45)(46)(47). Since these reviews were published, similar effects on mouse models of Alzheimer's disease (48), osteoporosis (49), fatty liver disease (50), and asthma (51) have also been reported.…”

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

“…In our study, PPN anti-OSA activity was related to direct cytostatic effects and cell cycle arrest, decreasing survival and mitosis in β-AR expressing tumor tissue. However, SNS activation and β-adrenergic signaling can regulate a wide range of cancer-associated molecular pathways via both direct effects on β-AR expressing transformed cells and regulation of other β-receptor-bearing cells populating the complex tumor stroma, such as vascular or immune cells [47,48]. In spite of using T cell-de cient nude mice for our in vivo studies, this animal model still has a robust innate immune response involving dendritic cells, tumor-associated macrophages and natural killer cells, which are known to play a key role against OSA [49].…”

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer

“…Resistance to immunotherapy developing in some initially responding tumors is now a clinical problem. Some evidence demonstrated that adrenergic stress inhibits immune response and its blockage might increase therapeutic efficacy of immunotherapy [98]. It was already studied that beta-adrenergic blockers reduced PC-related mortality [99].…”