Our own immune system is one of our greatest allies in suppressing the development of cancer in our bodies, but it often needs a little push. One way of doing this is by using a class of medications called ‘checkpoint inhibitors.’ These medicines release the brakes on certain immune cells—called killer T cells—that then try and kill cancer cells. These can be very effective treatments for certain kinds of skin, lung, and kidney cancers, but unfortunately, they don’t work for every patient.
A flurry of studies published in 2018 demonstrated that the patients’ microbiome may have something to do with this. People who did or didn’t respond to checkpoint inhibitor therapy were found to have consistent differences in the bacteria commonly found in their gut. And in 2021, two studies found that transferring microbes from the fecal matter of people who did respond to the therapy to the gut of those who didn’t, could improve therapeutic benefits in the latter patients.
Now an unexpected discovery in mice, published in the April 25 issue of the journal Science, hints at one factor that might explain why people respond differently to cancer therapy: the level of vitamin D in their gut tissue might promote the presence and growth of certain bacteria that stimulates killer T cells to attack the cancer.
Vitamin D, which we can get from our diet—by eating things like fatty fish or egg yolks—or produce in our skin when exposed to sunlight, plays a crucial role in our metabolism and the health of our bones, muscles, nerves, and immune system. There had been evidence that it might play a protective role in cancer as well, but the new findings in mice were still a surprise.
(Want to strengthen your bones? Look beyond vitamin D)
Testing whether the same mechanisms operate in humans will require careful further study, says Caetano Reis e Sousa, an immunologist at the Francis Crick Institute in London, England, and the senior author of the study, but it’s worth investigating.
“Vitamin D impacts the activity of hundreds of genes, so it’s complicated,” says Reis e Sousa. But in several datasets he and his colleagues have analyzed, patients with higher vitamin D activity had a higher chance of surviving various cancers, and responded better to immunotherapy.
The researchers also found evidence that in Denmark, where the sunshine that helps humans produce vitamin D in their skin is relatively rare, detailed health records reveal that people who had a lack of vitamin D had an elevated risk of developing cancer in the following decade. “This is probably an underestimate,” says Reis e Sousa, “because at least some of these people probably decided to take vitamin D supplements after learning about the deficiency.”
This study provides yet another reason to make sure you produce or consume enough vitamin D, says Carsten Carlberg, a biochemist at the Polish Academy of Sciences in Olsztyn who has studied the impacts of the vitamin for decades, and was not involved in the Science study. He warns, however, that it would be unwise to rush to conclusions about ourselves based on findings in mice. “There are 75 million years of evolution separating mice and humans.”
An intriguing observation
Reis e Sousa has long been interested in genes that affect the immune system’s ability to attack cancer cells. To identify these genes, researchers in his lab work with mice in which a gene that they suspect is involved in either promoting or suppressing cancer, has been switched off. By transplanting cancer cells into these modified mice, they can track how long it takes for the cells to grow into a tumor.
When his colleague Evangelos Giampazolias, now at the Cancer Research UK Manchester Institute, discovered that switching off the gene which provides instructions to make the aptly named vitamin D-binding protein reduces the growth of skin cancer cells in mice, Reis e Sousa was intrigued.
But it was the next experiment, he says, “that really did my head in.”
Just to make sure their discoveries weren’t due to some quirk in the lab environment, Reis e Sousa’s team raised mice with the disabled gene in the same cage as mice that carried a fully functional version.
To their surprise, it turned out that the cage mates’ tumors were also growing more slowly. But why would proximity to a more cancer-resistant animal slow down tumor growth in normal mice as well?
The power of poop
One explanation for this, Giampazolias and Reis e Sousa soon realized, was that mice eat each other’s poop; and that something in that poop must have been transferred from the mice with the deactivated gene to the normal mice they were caged with.
To test whether the effect had something to do with the gut microbes living in the genetically modified mice, Reis e Sousa’s team gave some of the mice with the deactivated gene a course of antibiotics. When that made the cancer resistance and their ability to pass it on to their cage mates disappear, it became clear the gut bacteria in mouse poop were somehow slowing the tumor growth.
Vitamin D-binding protein keeps most of the vitamin D in the blood, Reis e Sousa explains. “This reduces the amount of vitamin D that reaches the body’s tissues, including those lining the gut.”
The higher levels of vitamin D that resulted when Reis e Sousa’s team disabled the gene encoding vitamin D-binding protein promoted the growth and presence of a particular bacterium—Bacteroides fragilis—which is common in the human colon as well. And those bacteria, Reis e Sousa explains, may stimulate the immune system.
Switching off the gene, increasing the amount of vitamin D in the food of genetically normal mice, or adding more Bacteroides fragilis to the mouse gut all had the same effect: more killer T cells attacking the tumor, and slowing down its growth.
As a result of these higher vitamin D levels, the mice also had a better response to immunotherapy.
“We don’t know yet how the bacteria do this,” says Reis e Sousa. “But the effect is unmistakably there.”
New therapies
Reis e Sousa, who is of Portuguese descent and whose darker complexion means that he produces less vitamin D in sun-starved London, found out he was lacked enough of the vitamin about a decade ago, and has taken supplements ever since. “As a general rule,” he says, “if you’re diagnosed as deficient in vitamin D, it seems sensible to try and correct it. But that doesn’t depend on this study, of course.”
He adds that people should always consult their primary care physician before taking vitamin supplements—even if one learns they have a vitamin D deficiency—until more is known about the impact of vitamin D supplements on cancer risk and other aspects of human health. “There might be negative effects that we haven’t found out about, such as increased risk of autoimmune disease.”
(Some vitamins and minerals simply work better when eaten together)
He also warns against spending too much time in the spring sun to dose up on vitamin D.
“We do not advocate to increase sun exposure, which can also increase the risk of skin cancer, negating any benefit. You don’t need to go sunbathing for vitamin D, just going for a walk is probably enough.”
More importantly, says Reis e Sousa, the study will hopefully inspire new research to find out if supplements of either vitamin D or Bacteroides fragilis might improve the outlook for cancer patients undergoing immunotherapy or other treatments.
Walter Willett, a physician and nutrition researcher at the Harvard T.H. Chan School of Public Health who was not involved in the current study, agrees the data in Reis e Sousa’s new study suggest likely benefits of vitamin D for human cancer patients. “This is consistent with some of our own findings. We have found lower risks of colorectal cancer in women with high blood levels of vitamin D. I have also been involved in a trial showing lower cancer mortality in people receiving vitamin D supplements.”
Willett thinks vitamin D supplements are probably a good idea. “It makes sense for most people living in northern climates to take supplemental vitamin D and not bother with the expense of testing for vitamin D levels. The best way to do this is as a standard multi-vitamin/multi-mineral supplement containing 800 or 1000 International Units of vitamin D, which costs less than 10 cents per day.”
Whether the benefits of vitamin D in humans are mediated by the microbiome needs confirmation, Willett adds. “This will require new, large studies running over multiple years.”
There are many clinicians currently exploring whether it is beneficial to manipulate the microbiome to improve cancer therapy, Reis e Sousa says. “They can be remarkably successful in improving therapy outcomes, but they can also be dangerous, especially when people are immunosuppressed. We hope our discoveries may lead to more refined therapeutic applications.”
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