Obesity Plays Paradoxical Role in Cancer, Study Shows

Obesity Plays Paradoxical Role in Cancer, Study Shows

Obesity is known to promote cancer, but, paradoxically, obese cancer patients may respond better to cancer immunotherapy, a recent study has found.

The study, “Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade,” was published in Nature Medicine.

It’s been well-documented that obesity can increase a person’s chances of developing cancer; it’s also associated with worse cancer prognoses. This is in part because obesity is linked to an impaired immune system.

Cells that are acting irregularly — such as virus-infected or cancer cells — are typically targeted and eliminated by cells in the immune system. When a tumor develops, however, its cells find ways to avoid this immune-mediated killing. One of the ways cancer cells avoid the immune system is by expressing checkpoint proteins.

Healthy cells use checkpoint proteins to communicate to the immune system that they are healthy and don’t need to be destroyed. However, cancer cells co-opt this system, effectively “tricking” the immune system into treating the cancer cells just like healthy cells.

This is where checkpoint inhibitors, the kind of therapy investigated in the study, come in. As their name suggests, these inhibitors can block checkpoint molecules, which can allow the immune system to destroy tumor cells, leading to remission in the best cases.

But how does obesity affect cancer patients’ responses to these checkpoint inhibitors?

To find out, investigators from University of California, Davis, studied obese and non-obese mice, non-human primates, and humans. They found that, in all three species, being obese was associated with a less functional immune system. This included effector immune cells producing more checkpoint-recognizing proteins, so they might be more susceptible to the “tricks” cancer cells employ.

Obesity also promoted the growth of tumors in all the models studied.

“In obese animals cancer grows faster because there are more nutrients for tumors and because the immune system is more suppressed,” William Murphy, PhD, a co-author of the study and vice chair of research in the UC Davis Department of Dermatology, said in a press release.

The investigators found that leptin, a hormone closely linked to fat storage and, therefore, obesity, was also involved in tumor growth and immune regulation. Obese mice and patients had higher leptin levels, which correlated with more checkpoint molecules and decreased immune function. This suggests this hormone might be one of the many factors involved in lower immune function in obese patients.

When obese mice with cancer were given checkpoint inhibitors, they fared better than their non-obese counterparts, showing significantly decreased tumor size, fewer metastases, and enhanced immune activity. Further study of 251 melanoma patients treated with checkpoint inhibitors showed a marked survival benefit in obese patients — 17 months versus 12 months.

“We are not advocating for obesity as improving prognosis for cancer patients. But obesity appears to induce immune suppression and accelerated tumor growth through mechanisms that can be successfully reversed by checkpoint inhibitor immunotherapy,” said Arta Monjazeb, MD, PhD, a co-author of the study and associate professor in the UC Davis Department of Radiation Oncology.

Further studies will be needed to confirm this result and to further clarify how the many factors that make each patient unique — including age, weight, gender, diet, microbiome — interact and affect tumor growth so that the ideal therapy can be given to each patient.

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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