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Modulation of Anti-Tumor Immunity by the Brain’s Reward System

A discussion of new research which shows a link between stimulation of the brain's reward system and significantly decreased tumor size.

Introduction

Some individuals strongly believe that psychological health plays a vital role in warding off illness. However, reliable scientific data proves the connection is limited and inconsistent. Researchers affiliated with the Israel Institute of Technology aimed to investigate the possible effects stimulation of the reward system in the brain would have on tumor growth and to explore potential implications for cancer treatment. To do so, they conducted a study using tumor-bearing mice. They injected some of the mice with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and had a control group which did not receive these injections. All of the mice received daily clozapine-N-oxide (CNO) injections, which stimulated the Ventral Tegmental Area (VTA), the reward center of the brain, in only the experimental group.

Figure #1

Screenshot 2018-07-25 12.05.45

Image outlining the experimental design (Source 1)

The experimental group exhibited significantly smaller tumors in multiple trials, demonstrating a connection between VTA stimulation and tumor growth. The researchers performed another study to show that the results are due to Myeloid Derived Suppressor Cells (MDSCs), immune cells that develop in the bone marrow, becoming less immunosuppressive after reward center stimulation. This allows the immune system to better fight off the tumor.

Figure #2

Figure 2 (Gen Science Poster).jpg

MDSCs promote tumor growth in two main ways (Source 2)

Results

Compared to the control group, the mice that had been injected with DREADDs and CNO had tumors that were an average of 46.5% smaller and 52.4% lighter at the end of 14 days (Figure 3). This effect was observed in two different cancer models: Lewis Lung Carcinoma and B16 Melanoma, showing that the effects were not restricted to one type of cancer. The researchers also tested the effects of less frequent VTA stimulation by only injecting the mice with CNO every other day. In this study, the mice which had undergone reward system stimulation had tumors that were an average of 28% lighter than the control group after 14 days.

Figure #3

Screenshot 2018-07-25 11.58.36

Side by side tumor comparison for the first part of the experiment (Source 1)

Figure #4

Screenshot 2018-07-25 12.02.01.png

Side by side tumor comparison for the second part of the experiment (Source 1)

To find the reason behind the difference in tumor size, the researchers isolated MDSCs from the tumors of both the experimental and control mice and transferred them to a separate group of tumor-bearing mice. The new experimental group received MDSCs from the VTA-activated mice while the control group received MDSCs from the other mice. It was found that the experimental groups’ tumors were an average of 42.9% smaller and 43.6% lighter when measured (Figure 4). Being that the only differing variable was the origin of the MDSCs, the researchers came to the conclusion that MDSCs are likely the mechanism that links VTA-activation and tumor growth.

Conclusions

In this study, the research team demonstrated a connection between reward center activation and cancer progression. The results are consistent with those of previous studies, including one which showed a correlation between decreasing levels of depression and longer lifetimes in women with breast cancer. Many of the researchers in this study also participated in a 2016 study in which they found VTA-activation played a role in the immune system response to bacterial infection. Those results inspired the team to research the connection further, which they did in this study. This study is groundbreaking because it focuses on the influence of positive emotions rather than negative ones and it provides an explanation of the processes responsible for the effect. In the future, the researchers hope to explore other mechanisms that may contribute to the observed connection and study other cancer stages, such as tumor initiation and metastasis, that reward center stimulation may play a role in. Their ultimate goal is to gain deeper insight into the workings of cancer and to apply their research to cancer treatment in humans.


References:

  1. Ben-Shaanan, T. L., Schiller, M., Azulay-Debby, H., Korin, B., Boshnak, N., Koren, T., Maria, K., Jivan, S., Michal, R. A., Fahed, H., Rolls, A. (2018). Modulation of anti-tumor immunity by the brain’s reward system. Nature Communications, 9. Retrieved from https://www.nature.com/articles/s41467-018-05283-5.
  2. Gabrilovich, D. I., Nagaraj, S. (2009). Myeloid-derived-suppressor cells as regulators of the immune system. Nat Rev Immunol, 9(3). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/.
  3. Giese-Davis, J., Collie, K., Rancourt, K. M.S., Neri, E., Kraemer, H. C., Spiegel, D. (2011) Decrease in Depression Symptoms Is Associated With Longer Survival in Patients With Metastatic Breast Cancer: A Secondary Analysis. Journal of Clinical Oncology, 29(4). doi: 10.1200/JCO.2010.28.4455
  4. Ben-Shaanan, T. L., Azulay-Debby, H., Dubovik, T., Starosvestsky, E., Korin, B., Schiller, M., Green, N. L., Admon, Y., Hakim, F., Shen-Orr, S. S., Rolls, A. (2016). Activation of the reward system boosts innate and adaptive immunity. Nature Medicine, 22, 940-944. Retrieved from https://www.nature.com/articles/nm.4133.

Acknowledgments

I would like to thank the Brandeis Genesis precollege program for the amazing experience I had there and for allowing me to create and present my work. This article, which is adapted from a poster I made during the program, is based on recent research, the link to which is provided in source 1. I am grateful to Questbridge and the Ed Fein Foundation for allowing me to access the Genesis program. I would also like to thank my Science, Society, and Ethics instructors, Abraham and Casey, for all of their assistance.

 

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