The paradoxical role of obesity in immunotherapy response

Obesity is a major risk factor for cancer as it both feeds tumors and weakens the immune system. It also increases toxicities of immunotherapy treatments. It is hard to imagine that anything good could ever come from obesity. Yet a new research published on Nature Medicine suggests that obese patients respond better than others to immunotherapy. What is behind this paradoxical effect?

Only a small fraction of patients responds to immunotherapy. The comprehension of the factors behind such variability is crucial to select the best treatment for each patient and increase the percentage of responders. Obesity is definitely a risk factor for cancer and it negatively affects the immune system: who would have thought that overweight patients had a greater chance to respond to immunotherapy than those with a normal body mass index (BMI)?

Obesity and immune system do not get along

This paradox has an explanation. Tumors grow faster in obese subjects not only because they are provided with additional nutrients, but also because they find an immune-suppressed environment. Studying T cells in obese mice made scientists realize that most are “exhausted”, an immunological definition meaning that they are slow to proliferate and do not produce chemical messengers to communicate with other immune cells. In addition, these T cells express higher levels of a protein called PD-1, which is engaged by the tumor to block their activity.

Scientists working with immunotherapy are familiar with PD-1. This is the protein targeted by the so-called “immune checkpoint inhibitors”. The cutting-edge results of immunotherapy are largely due to the success of these drugs in the treatment of melanoma or lung cancer. The block of the interaction between PD-1 and the tumor restores the normal functions of T-cells: once their brakes are released, they can go after cancer.

Obesity and immunotherapy may get along (but not too much)

The unexpected role of obesity in response to immunotherapy becomes clearer now. The mechanisms by which tumors prosper in an overweight organism are the same targeted by immunomodulatory drugs. The increase of PD-1 expression on the surface of T-cells is probably a consequence of obesity. Scientists think that leptin has a hand in this. Leptin is the hormone controlling the sense of satiety and is produced in higher amounts in overweight people; but it also affects the immune system, probably modulating its interaction with the tumor.

Cancer takes advantage of this situation, of course: but for once, it uses the “wrong” strategy. In fact, we are particularly good at blocking the PD-1/tumor interaction. This explains not only why obese people often benefit more from immunotherapy, but also why they can suffer from serious side effects. If not properly balanced, immunotherapy may overstimulate the immune system to an extent that becomes dangerous for the organism.

Any idea for new treatment?

Despite its paradoxical role in cancer therapy, dietary or pharmacological treatments in order to mimic some effects of obesity may do more harm than good to patients. The BMI may become a prediction factor to select patients that are more likely to benefit from the treatment, though. However, there is a very careful balance there and it is probably early to make decisions based on BMI. In the meantime, this adds another piece to our understanding of the mechanisms behind variability in responses to immunotherapy.

Erika Salvatori

Reference:

Wang, Z. et al. (2018). Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine.