At Oncobites, we’ve been talking a lot about the role of immunity in cancer. Understanding the immune system is vital to understanding both what drives cancer and what protects us against it. One of the biggest paradoxes in cancer research is that immune system activation is important in fighting cancer via a process called immune surveillance, but can also promote tumor growth and invasion. This is a direct result of the complexity of the immune system; some immune cells can identify overexpressed or foreign proteins on the surface of cancer cells and react by hunting them down and killing them, but some can also treat the tumor like a wound, secreting proteins that form new blood vessels and remodel surrounding tissue, thus stimulating growth and metastasis. Some even serve to suppress immune activity altogether, which can also lead to tumor growth.
We know that the immune system plays a huge role in tumor biology, but we are still learning about what that role is and how factors affecting the immune system might change it. One hotly debated topic in the field of oncology is how emotional and mental state, which can affect immunity, might affect cancer biology. Neuroimmunology is a rapidly growing field focused on the interaction between the immune and nervous systems, which were long thought to be mostly separate. You may have heard that it’s easier to get sick when undergoing chronic stress; that’s a result of these two systems interacting, though we still aren’t sure what’s causal and what’s just amplified by this interaction independent of cause. In other words, when it comes to how mental state affects immunity and eventually tumor biology, we don’t quite understand the physiological mechanism yet and we don’t know what comes first (the chicken or the egg? Stress or immune dysregulation?).
Now, we are starting to probe this relationship more in order to reveal pathways by which changes may occur. A recent study published by Tamar L Ben-Shaanan et al. showed that activation of the brain’s reward system directly impacted tumor growth through mediation by the sympathetic nervous system (SNS), which is responsible for the body’s “fight-or-flight” response to danger. Researchers genetically engineered mice so that their reward system neurons (and only those neurons) could be specifically activated by dosing with a synthetic drug. In two different tumor models, tumor size and weight were reduced by at least 35% and up to 50% in these mice after daily reward system activation for 2 weeks. However, this effect is not direct. Further investigation revealed that the chemical noradrenaline (NA), which is regulated by the SNS, was significantly reduced in the bone marrow of tumor-bearing mice after reward system activation. This makes sense intuitively; activation of the brain’s reward system should reduce the response associated with “fight-or-flight.” Importantly, the bone marrow is where new immune cells are made. During cancer progression, myeloid-derived suppressor cells (MDSCs), which serve to suppress the immune system, expand substantially. Why does this matter? The researchers found that NA signaling causes MDSCs to reduce expression of TNF-α, an anti-tumor protein, and enhances their ability to suppress the activity of cancer-fighting killer T cells.
Because of this finding, the researchers isolated bone marrow MDSCs from the reward-system-activated-mice and transplanted them into normal tumor-bearing mice in order to determine if the reduction in tumor size and weight could be attributed to MDSC activity following this change in bone marrow NA levels. Tumors were again significantly reduced, demonstrating the causal nature of this pathway. To summarize, they found that synthetic activation of the brain’s reward system led to decreased levels of NA in the bone marrow, which reduced the immunosuppressive properties of MDSCs, thus enhancing anticancer immune activity and reducing tumor size and weight.
While it is important to note that synthetic reward system activation is not translatable for human cancer treatment, this study still provided interesting mechanistic details for how mental state may play a role in disease progression biologically, especially since the reward system plays a principal role in mood regulation. Given the inherent difficulties of studying psychological effects on cancer biology, this represents a huge step forward in experimental design that can enable scientists to investigate cancer more holistically and discover new targets for treatment through systems thought to be independent of each other in years past.
Ben-Shaanan, T. L., Schiller, M., Azulay-Debby, H., Korin, B., Boshnak, N., Koren, T., … & Rolls, A. (2018). Modulation of anti-tumor immunity by the brain’s reward system. Nature Communications, 9. doi: https://doi.org/10.1038/s41467-018-05283-5