Can vitamin D improve cancer immunotherapy?

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Whether through sunlight or capsules, it is important that everyone gets their daily dose of vitamin D. This essential vitamin is known to help the body absorb calcium, the foundation of healthy bones and teeth. New research says this nutrient may have another unknown benefit: it helps the body fight cancer. Preclinical findings published in the magazine Science suggest that vitamin D intake may influence the immune system through the gut; this in turn could improve antitumor responses to a class of cancer immunotherapies called checkpoint inhibitors.

Checkpoint inhibitors and the gut microbiome

Central to this research is the vague but continually clarifying axis between the gut microbiome, the immune system and cancer.

Over the past twenty years, new connections have emerged between the gut microbiome – the trillions of microorganisms that live in our stomachs, intestines and large intestines – and the immune system. Researchers note that changes in the microbiota can influence the incidence and progression of cancers outside the colon breast and liver cancer. The microbiome could also be an important factor in improving checkpoint inhibitors, an antibody-based immunotherapy used to treat several types of cancer.

Multiple intestinal bacteria It turns out that strains in mice improve antitumor responses to checkpoint inhibitors. To take antibiotics, which damages the intestinal flora, is also correlated with worse responses to this inhibitor therapy; oral supplements can restore these responses in antibiotic-treated mice. Moreover, studies have shown this melanoma patients those who respond to PD-1 checkpoint inhibitors tend to have more “good” bacteria; non-responders had an imbalance in intestinal flora, which was correlated with reduced immune cell activity.

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Taken together, these findings suggest a complex interplay between the gut and the gut immune pathways that checkpoint inhibitors affect. By targeting the microbiome through supplements, diet, or other means, it may be possible to significantly improve outcomes for patients undergoing this therapy.

What we know about vitamin D

In their work, researchers from the Francis Crick Institute in London investigate the link between the gut microbiota and its effect on cancer immunity via vitamin D.

Most people are familiar with vitamin D and its effect on bones. Vitamin D, also known as calciferol, is a fat-soluble nutrient that promotes the absorption of calcium. The nutrient is found in two forms: vitamin D3 and vitamin D2. The skin can produce vitamin D3 through exposure to ultraviolet B in sunlight. The nutrient also occurs naturally in animal foods, including fatty fish such as salmon and tuna. Vitamin D2, on the other hand, comes from a limited selection of plants. Both forms are broken down into smaller molecules in the liver and kidneys.

Perhaps less known is the effect of vitamin D on intestinal immunity. T cells, B cells and other immune cells in the intestines are expressed vitamin D cell receptors, indicating its role in maintaining intestinal immunity. Vitamin D deficiency is also associated with an increase autoimmunity and risk of infection. Can vitamin D interact with intestinal cells to influence antitumor immunity?

New study: mouse microbes and vitamin D

To investigate the link between vitamin D and tumor resistance, researcher Giampazolias and colleagues turned to mouse models of melanoma. The mice were deficient in globulin, a protein that transports vitamin D throughout the body. Animals with less globulin in the blood appear to have higher levels of vitamin D in the tissues. Based on this thinking, the team expected that mice with less globulin – and therefore more vitamin D – would show better anti-tumor responses.

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When given a tumor challenge, globulin-deficient mice perform better than mice with sufficient globulin. They control tumors better, exhibit higher intratumoral levels of activated T cells, and respond more readily to checkpoint inhibitor therapy.

The anticancer responses to vitamin D appear to be dependent on the microbiome. Normal mice should exhibit poorer tumor control compared to globulin-deficient mice. However, these mice can acquire this tumor resistance if they are housed with globulin-deficient mice for a while. Similarly, fecal transplantation of deficient mice can improve tumor control in microbiota-rich mice.

This mechanism appears to depend on the availability of vitamin D. When normal and globulin-deficient mice are fed a diet without vitamin D for four weeks, both cohorts suffer rapid tumor progression. Conversely, increased vitamin intake leads to increased vitamin D levels in the blood and reduced tumor growth in normal mice; these levels are comparable to their globulin-deficient counterparts.

Mice lacking microbiota did not experience improved antitumor activity when placed on a high vitamin D diet, and fecal transplants from vitamin D-deficient mice failed to confer tumor resistance. Both results underline a link between vitamin D antitumor responses and the microbiome. This interaction likely works through vitamin D uptake into intestinal epithelial cells, according to gene expression analysis of colon tissue.

Vitamin D and cancer in humans

The researchers also extended their findings to humans. They examined gene signatures of vitamin D activity in various cancers using data from The cancer genome atlas and found that lower expressions of vitamin D activity correlate with worse patient outcomes. Furthermore, an analysis of more than a thousand patients treated with checkpoint inhibitors linked lower tissue availability of vitamin D to faster cancer progression.

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The team also turned to data from a large cohort of Danish participants who had at least one vitamin D serum measurement before their first cancer diagnosis. They noted that low serum vitamin D levels correlate with an increased risk of cancer over a decade, highlighting vitamin D as a potential risk factor for the development of cancer in humans.

Future implications

While checkpoint inhibitors represent a remarkable advance in cancer care, they yield mixed results. In some patients they produce lasting responses; for others, no responses at all. Although further research is needed to determine the exact mechanism, this study points to vitamin D as a possible solution. If the link between this nutrient and antitumor responses in humans holds true, cancer patients undergoing checkpoint inhibitor therapy could increase their vitamin D intake to improve tumor resistance—a simple diet change with potentially enormous benefits. This study joins a sea of ​​research on the potential of microbes to improve checkpoint inhibitor therapy.

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