A recent study in the journal Nature Medicine by Wang et al, (Wang et al ., 2018) found that obesity appears to have contradictory effects on cancer and responses to cancer treatment. The study demonstrates that obesity can have a negative effect on the immune system by promoting immune cell exhaustion and tumour growth. Paradoxically, obesity was found to improve the effects of cancer fighting immunotherapy.

obesity

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Obesity is a word we are accustomed to reading and hearing about, whether it is in the latest report highlighting the obesity epidemic in children, or the current actions being taken by policy makers to tackle the growing problem.  Alarmingly, spending on care for obesity and its comorbidities accounts for over 20% of the total annual US healthcare spending (Cawley and Meyerhoefer, 2012)  therefore the impact on society is significant.

In practical terms, an obese person has a BMI of over 30 (kg/m2), therefore they contain too much body fat for their height and gender.  Obesity is associated with other life-limiting conditions such as heart disease, diabetes and cancer.

Immunotherapy, a relatively new cancer treatment involves the use of antibodies or viruses to target tumour cells. A recent immunotherapy has been developed to target the molecular  pathway  PD-1/PD-L1 (PD-(L)1), which signifies that the immune T cell is damaged. Therapy targeting this pathway is also known as ‘checkpoint blockage’ and has been successful at treating many cancers such as melanoma and lung cancer, but many patients do not respond for unknown reasons.

Interestingly and perhaps alarmingly, checkpoint blockage immunotherapy has been demonstrated to improve responses and survival in obese cancer patients.

Wang and colleagues investigated these apparently contradictory reporting’s. They initially demonstrated that obese mice, non-human primates and humans had higher levels of dysfunctional T cells that could not replicate properly and expressed PD-(L)1 on their surface.

The authors then found that obesity promoted the growth of breast and skin cancer tumours in different strains of mice and it promoted the exhaustion of their T cells. T cell exhaustion is characterised as the progressive loss of cell function, therefore the cells cannot respond to invading disease-causing agents and importantly, cannot kill tumour cells.

Obesity is associated with what is known as a ‘metainflammatory state’ where the body is in a constant state of low level inflammation. This causes a rise in the number of immune cells circulating in the body and generation of other important molecules such as Leptin. Leptin in made by fat cells called adipocytes and its role in the body is to stop a person from feeling hungry, therefore stopping them over eating and becoming obese.

Surprisingly Wang et al found increased levels of Leptin in their obese mice and in the blood of obese human subjects. The elevated Leptin levels were associated with higher PD-1 and with T cell exhaustion. Therefore, the authors’ proposed that Leptin may be the previously unknown link between obesity and dysfunctional T cells. In line with this theory, the authors also found the Leptin caused tumours in mice to grow faster and it inhibited the mouse immune system from fighting the tumour.

PD-1 appeared to be critical in causing some of these detrimental effects to the immune cells and therefore stopping them from killing the tumour cells. To see whether the authors could rectify this, they treated the mice with checkpoint blockade immunotherapy. Remarkably, they found that the tumour burden in the obese mice was reduced and the treatment increased the mice overall survival. What was even more remarkable was that the effect of the immunotherapy was much higher in obese mice than in non-obese mice, therefore obesity appeared to promote the beneficial effects of the immunotherapy!!!

Finally, when the authors administered this therapy to 250 obese and non-obese cancer patients they found that the obese patients had better clinical outcomes to the therapy compared to the patients of a healthy weight. The obese patients had improved overall survival.

This is the first time that obesity has been directly link to immune cell aging and dysfunction which appears to be driven by Leptin produced by fat cells. The data produced by Wang and colleagues backs up other reports that found that obese cancer patients successfully responded to immunotherapy.

While the paradoxical effect of obesity on cancer and cancer treatment has still to be fully investigated, this study significantly contributes to the growing body of evidence which helps doctors and scientists understand what factors affect patient responses to therapy. This study will hopefully pave the way for doctors to tailor treatment to individual cancer patients in the future.

References:

CAWLEY, J. & MEYERHOEFER, C. 2012. The medical care costs of obesity: an instrumental variables approach. J Health Econ, 31, 219-30.

WANG, Z., AGUILAR, E. G., LUNA, J. I., DUNAI, C., KHUAT, L. T., LE, C. T., MIRSOIAN, A., MINNAR, C. M., STOFFEL, K. M., STURGILL, I. R., GROSSENBACHER, S. K., WITHERS, S. S., REBHUN, R. B., HARTIGAN-O’CONNOR, D. J., MÉNDEZ-LAGARES, G., TARANTAL, A. F., ISSEROFF, R. R., GRIFFITH, T. S., SCHALPER, K. A., MERLEEV, A., SAHA, A., MAVERAKIS, E., KELLY, K., ALJUMAILY, R., IBRAHIMI, S., MUKHERJEE, S., MACHIORLATTI, M., VESELY, S. K., LONGO, D. L., BLAZAR, B. R., CANTER, R. J., MURPHY, W. J. & MONJAZEB, A. M. 2018. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine.

https://www.nature.com/articles/s41591-018-0221-5#ref-CR13

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