Paradox: Obesity Promotes Tumors but Boosts Immunotherapy

Fran Lowry

November 28, 2018

Being obese increases the risk of developing cancer, but paradoxically, in cancer patients, excess weight helps immunotherapy drugs kill cancer cells, according to a study published online November 12 in Nature Medicine.

Researchers at the University of California (UC), Davis, School of Medicine, Sacramento, California, have demonstrated both in animals and in humans that obesity increases immune aging, tumor progression, and programmed cell death protein–1 (PD-1)–mediated T-cell dysfunction, which is partly driven by leptin.

They also showed that obesity is associated with increased efficacy of PD-1/programmed cell death–ligand-1 (PD-L1) blockade (checkpoint blockade) in both tumor-bearing mice and in cancer patients.

"These data indicate a paradoxical impact of obesity on cancer," coauthor William J. Murphy, PhD, distinguished professor at UC Davis School of Medicine, told Medscape Medical News.

"There is heightened immune dysfunction and tumor progression but also greater antitumor efficacy and survival after checkpoint blockade, which directly targets some of the pathways activated in obesity," Murphy commented. He is a co–senior author of the article with Arta M. Monjazeb, MD, PhD.

For the past 25 years, Murphy has been evaluating cancer therapies, in particular, immunotherapies, using the laboratory mouse as his model.

"I noticed that when we use young, genetically identical mice that are really clean and specific-pathogen free, that they could handle the immunotherapy, but when we looked at obese or older mice, they showed a lot of toxicities. This mirrored some of the toxicities that we have seen clinically, and so what this was telling us was that our mouse model needed to be improved when we started looking at obesity," he said.

The fact that checkpoint blockade with PD-1 showed clinical efficacy led Murphy and his team to test it in his new obese mouse model.

"We expected that either the PD-1 blockade would have less of a therapeutic effect or would result in autoimmunity. To our surprise, we found in our obese mouse models, that PD-1 blockade actually resulted in greater antitumor effects without the toxicities," he said.

Murphy and his laboratory then joined forces with the University of Oklahoma Health Sciences Center, Oklahoma City, where they found that in cancer patients who had a high body mass index (BMI), survival after checkpoint blockade was better than in leaner cancer patients.

"The clinical study mirrored what we saw in the mice. We saw the exact same paradigm between mouse and man, that obesity, at first glance, is actually bad, because we found the tumors grew faster, but we also found that obesity also causes suppression of the immune system and increased expression of checkpoint proteins and that the action of checkpoint inhibitors was enhanced in obese subjects," he said.

The researchers studied the differences in T-cell function in obese and nonobese mice and found that T-cell function was diminished and the expression of the PD-1 protein on the T cells was higher than in the nonobese control mice.

They saw a similar pattern when the studies were conducted in both macaque monkeys and in human volunteers. Further experiments showed that tumors grew more aggressively in obese mice, regardless of the type of tumor.

"We found that in obese animals and humans, that their immune systems were more suppressed, but once we took the brake off, meaning when we used checkpoint blockade, their immune systems actually worked better than that of their immune counterparts," he said.

"This was telling us that this is probably a normal function when you have an obese situation. Obesity is considered an inflammatory or meta-inflammatory state, and the immune system is normally geared to keep things at bay by suppressing itself. What we are doing is taking the brake off, and with all that sort of 'gasoline rich' environment, the T cells do really well compared to those in their lean counterparts," Murphy said.

There may be other advantages to being obese when it comes to cancer, he said.

"In obese situations, there are more nutrients and reserves, so that when an individual, or a mouse, or whatever, is going through therapies, they can withstand weight loss and stressors better. There probably are other advantages, too," Murphy said.

He is now exploring whether a high-fat diet could yield results similar to those seen in association with high BMI.

"In the obesity situation, we find the immune system has enough nutrients to function better than in a lean situation, and so we are still trying to figure out with regard to our obesity studies what is the formula for success. Do you have to have an obese situation, or can you have a diet where you provide the nutrients that allow the immune system to work better? It could be that timing could be critical," Murphy said.

The Take-home for Clinicians

In this era of personalized medicine, a patient's BMI is an important factor to take into account when considering treatment.

"The clinical study from Oklahoma showed increased survival in high-BMI men with immunotherapy with PD-1 checkpoint blockade. This is changing the obesity paradigm, where it's not just bad, there are some positive things, too. We need to look at BMI as something to take into consideration with our patients, and then how to target the type of immunotherapy, or any therapy," Murphy said.

"We need to make our mouse models more like people, and that will definitely help us get more realistic insights as to therapies. Our work tells us that we should be looking in old and obese mice, because that's basically your cancer patient," he said.

The study was sponsored by the National Institutes of Health. Dr Murphy and Dr Monjazeb have disclosed no relevant financial relationships.

Nat Med. Published online November 12 , 2018. Abstract


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