Neuroimmunology of Behavioral Comorbidities Associated With Cancer and Cancer Treatments

Abstract

Behavioral comorbidities (depression, anxiety, fatigue, cognitive disturbances, and neuropathic pain) are prevalent in cancer patients and survivors. These mental and neurological health issues reduce quality-of-life, which is a significant societal concern given the increasing rates of long-term survival after various cancers. Hypothesized causes of behavioral comorbidities with cancer include tumor biology, stress associated with the cancer experience, and cancer treatments. A relatively recent leading mechanism by which these causes contribute to changes in neurobiology that underlie behavior is inflammation. Indeed, both basic and clinical research indicates that peripheral inflammation leads to central inflammation and behavioral changes in other illness contexts. Given the limitations of assessing neuroimmunology in clinical populations, this review primarily synthesizes evidence of neuroimmune and neuroinflammatory changes due to two components of cancer (tumor biology and cancer treatments) that are associated with altered affective-like or cognitive behaviors in rodents. Specifically, alterations in microglia, neuroinflammation, and immune trafficking to the brain are compiled in models of tumors, chemotherapy, and/or radiation. Evidence-based neuronal mechanisms by which these neuroimmune changes may lead to changes in behavior are proposed. Finally, converging evidence in clinical cancer populations is discussed.

Keywords: cognition; cytokines; depression; neuroinflammation; neuropathic pain.

Figure 1

Potential innate immune mechanisms by which peripheral cancer and cancer treatments can induce behavioral changes. (1) The tumor microenvironment releases pro-inflammatory mediators (e.g, cytokines) that can influence the brain and behavior through humoral or neural routes. (2) Chemotherapy induces cell death of tumor cells and healthy cells (in the brain and the periphery), thereby causing the release of DAMPs, ROS, cytokines, and chemokines and contributing to many side effects. For example, chemotherapy-induced peripheral neuropathy is associated with astroglial and microglial activation in the spinal cord and TLR4 activation in DRG neurons. Similar inflammasome activity may occur in the brain. Chemotherapy may also weaken the blood–brain barrier, allowing peripheral immune cells to traffic into/closer to the brain. (3) Peripheral radiotherapy induces cell death of tumor cells and healthy “bystander” cells and (indirectly) contributes to microglial activation and behavioral deficits. (4) Together, the tumor and cancer treatments influence microglia. Tumors and radiotherapy (indirectly) activate microglia, whereas chemotherapy may affect microglia differently over time. Microglia interface with neurons to affect behavior, potentially through. Certain elements of this work were taken and then adapted from somersault18:24 (Library of Science & Medical Illustrations). To view their site, visit http://www.somersault1824.com/. They are licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA.