Two new studies have provided compelling insights into the relationship between obesity and cancer. The research reveals fascinatingly paradoxical effects, suggesting obesity can suppress our immune responses to enhance tumor growth, but also improve the efficacy of a new kind of cancer-killing immunotherapy.
The first study, from Trinity College Dublin, focuses on the effect of obesity on a type of immune cell known as natural killer (NK) cells. These cells play a vital role in cancer surveillance, hunting the body for tumor cells, and activating an immune attack when they track then down.
The research revealed that excess fat can fundamentally blunt the anti-tumor responses of NK cells by essentially "clogging up" the cells and inhibiting their cytotoxic machinery. The study suggests that metabolic reprogramming of these NK cells could kick-start their anti-cancer activity, offering a potential new treatment strategy.
The second study, from UC Davis, homed in on another mechanism by which obesity drives tumor growth. It found that leptin, a hormone produced by fat cells in the body, mediated dysfunction in cancer-killing T-cells by increasing the presence of a protein called PD-1.
"In obese animals cancer grows faster because there are more nutrients for tumors and because the immune system is more suppressed," says William Murphy, co-author of the UC Davis study.
PD-1 essentially acts to turn down immune system activity, and cancer cells can cleverly stimulate that protein to avoid attack from the immune system. A new class of immunotherapy drugs called checkpoint inhibitors work by blocking PD-1 activation, releasing the brake on T-cells to help them better hunt, and kill, cancer cells.
Interestingly, previous research has revealed that these new checkpoint inhibitor drugs are more effective in obese patients. The new study further examined this odd paradoxical outcome confirming in both animal and human cohorts that PD-1 inhibitors are indeed more effective in obese patients compared to non-obese patients.
"It's counter-intuitive because up to this point all of our studies showed that obesity resulted in more toxicities associated with immunotherapy treatments," says Murphy. "This is a game-changer because when we personalize medicine and look at body mass index, in some situations it can be bad, and in some situations it can be helpful."
The hypothesis is that the excess of PD-1 brought on by obesity actually makes the checkpoint inhibitor drugs more effective in activating the body's T-cells. The UC Davis team do caution that this doesn't mean cancer patients embarking upon a new checkpoint inhibitor treatment run out and commence a high-fat diet to enhance the drug, but instead the discovery could help better home in on the most effective treatment for individual patients.
"We are not advocating for obesity as improving prognosis for cancer patients," says Arta Monjazeb, co-last author on the study. "But obesity appears to induce immune suppression and accelerated tumor growth through mechanisms that can be successfully reversed by checkpoint inhibitor immunotherapy."
It's clear that while obesity may improve the efficacy of certain new immunotherapies, it also certainly hampers the immune system, and causes tumors to grow more aggressively. Further research from the UC Davis team will explore whether this specific mechanism, that increases the effect of checkpoint inhibitors, can be harnessed to make the new immunotherapy treatment successful in more patients.
The first study was published in the journal Nature Immunology, while the second study appears in the journal Nature Medicine.
Sources: Trinity News, UC Davis
