In an interesting twist, scientists show that obesity may actually have a positive influence on cutting-edge cancer therapies. A new study published on 12 November in Nature medicine (1) has demonstrated a “contrasting and paradoxical impact of obesity on cancer.”
According to the World Health Organization (WHO), obesity is one of the greatest public health challenges of the 21st century and its prevalence in Europe has tripled since the 1980s, with numbers increasing at an alarming rate. Obesity is known to be one of the biggest risk factors for developing cancer ― up to 49% of certain types of cancer are attributed to obesity ― second only to smoking.
Only a small cohort of patients respond to powerful immunotherapy drugs for fighting tumours. Amazingly, a group of drugs, known as checkpoint inhibitors ― that work by blocking the activation of a protein on the surface of T cells called PD-1 ― have been reported to make untreatable tumours disappear for years in cases of melanoma, lung cancer, and other types. In some cases, overweight patients responded better than others ― those who were male and overweight lived much longer on average (2). So what could be the reason?
First, the team led by Dr William Murphy and Dr Arta Monjazeb from the University of California (UC), Davis showed that overweight people produce large quantities of leptin, a hormone produced by fat cells. Leptin signals to the brain when it is time to stop eating but it also plays a role in the immune system. The team suspects lectin may trigger a signalling pathway that increases PD-1 on T cells.
The PD-1 protein is normally produced by the body to dampen immune responses, however, tumours also stimulate the production of PD-1 so that they can go under the radar and rapidly multiply. The team showed that tumours grow faster in obese mice because the T cells of these mice are “exhausted” and easily suppressed by tumour cells. However, they also found that the T cells of obese mice have excess PD-1 and are unusually responsive to PD-1 inhibitors (checkpoint inhibitors), enabling them to attack cancer cells much more effectively.
According to another study published the same day in Nature Immunology (2), this is achieved by something called “metabolic reprogramming“ of T cells and the authors suggest there is “an urgent need to understand the pathways by which obesity leads to other diseases, and to develop new strategies to prevent their progression.”
Next, the researchers at UC Davis plan to study whether feeding a high-fat diet or leptin to normal-weight mice with cancer can boost their response to PD-1 inhibitors. In other words, can mimicking obesity in mice improve their response to cancer drugs? Perhaps, but there is a risk the adverse effects of obesity outweigh any potential benefits―a high-fat diet could end up having other harmful effects, such as cardivascular disease and diabetes.
The findings highlight an “unexpected” benefit” of obesity for cancer patients and could point to novel ways of making drugs more effective in all cancer patients. Nonetheless, any future therapies will require a careful balance and a better understanding of how all factors including BMI, sex, age, interact and can affect treatment.
(1) Wang, Z. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine (2018). DOI: 10.1038/s41591-018-0221-5
(2) McQuade, J. L. et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. The Lancet (2018). DOI: 10.1016/S1470-2045(18)30078-0
(3) Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nature Immunology (2018). DOI: 10.1038/s41590-018-0251-7