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Can Vitamin D Improve Cancer Immunotherapy?
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Yellow soft shell D-vitamin capsule.
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Whether by rays of sun or through capsules, it's important for
everyone to get 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 possess another
unknown benefit: helping the body fight cancer. Preclinical findings
published in the journal __ suggest that vitamin D intake can
influence the immune system through the intestines; this, in turn,
could improve antitumor responses to a class of cancer immunotherapies
called checkpoint inhibitors.
## **Checkpoint Inhibitors and the Intestinal Microbiome**
At the center of this research lies the hazy, but continually
clarifying, axis between the intestinal microbiome, the immune system,
and cancer.
Within the last two decades, new connections have emerged between the
gut microbiome—the trillions of microorganisms living in our stomachs,
intestines and colons—and the immune system. Researchers note that
changes in the microbiota can influence the incidence and progression
of cancers beyond the colon, including 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 cancers.
Several intestinal bacteria strains in mice are found to improve anti-
tumor responses to checkpoint inhibitors. Taking antibiotics, which
damage the intestinal flora, is also correlated with poorer responses
to this inhibitor therapy; oral supplements can restore these
responses in antibiotic-treated mice. Additionally, studies have
observed that melanoma patients who respond to PD-1 checkpoint
inhibitors tend to possess more "good" bacteria; nonresponders had an
intestinal flora imbalance, which was correlated with impaired immune
cell activity.
Altogether, these findings suggest a complex interplay between the
intestines and the immune pathways that checkpoint inhibitors affect.
By targeting the microbiome through supplements, diet or other means,
it could 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 intestinal microbiota and its effect on
anticancer immunity through vitamin D.
Most people are familiar with vitamin D and its effect on the bones.
Vitamin D, also known as calciferol, is a fat-soluble nutrient that
promotes calcium absorption. The nutrient can be found in two forms:
vitamin D3 and vitamin D2. The skin can produce vitamin D3 from
exposure to ultraviolet B in sunlight. The nutrient is also naturally
found in animal-derived foods, including fatty fish such as salmon and
tuna. In contrast, vitamin D2 is sourced from a limited selection of
plants. Both forms are broken down into smaller molecules in the liver
and kidneys.
Perhaps lesser known is vitamin D's effect on intestinal immunity. T
cells, B cells and other immune cells in the intestines express
vitamin D cell receptors, hinting at its role in maintaining
intestinal immunity. Vitamin D deficiency is also associated with
increased autoimmunity and risk of infection. Could vitamin D interact
with intestinal cells to influence antitumor immunity?
## **New Study: Mice 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 had a deficiency in globulin, a protein that
carries vitamin D throughout the body. Animals with less globulin in
the blood appear to possess higher levels of vitamin D in the tissues.
Following this train of thought, the team expected mice with less
globulin—and therefore more vitamin D—would show better antitumor
responses.
When given a tumor challenge, globulin-deficient mice outperform mice
with sufficient globulin. They control tumors better, display higher
intratumoral levels of activated T cells, and respond more readily to
checkpoint inhibitor therapy.
Vitamin D anticancer responses appear to be hinged upon the
microbiome. Normal mice should exhibit worse tumor control compared to
globulin-deficient mice. However, these mice can acquire this tumor
resistance if housed with globulin-deficient mice for a time.
Likewise, a fecal transplant from deficient mice can enhance tumor
control in microbiota-replete mice.
This mechanism appears to be dependent on vitamin D availability. When
normal mice and globulin-deficient mice are fed a diet devoid of
vitamin D for four weeks, both cohorts suffer rapid tumor progression.
Inversely, increased vitamin intake leads to elevated vitamin D levels
in the blood and decreased tumor growth in normal mice; these levels
are comparable to their globulin-deficient counterparts.
Mice without 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 underscore a connection between vitamin D antitumor responses
and the microbiome. This interaction likely acts through vitamin D
uptake in the intestinal epithelial cells, according to gene
expression analysis of colonic tissue.
## **Vitamin D and Cancer in Humans**
The researchers also extended their findings to humans. They examined
gene signatures of vitamin D activity in different cancers using data
from The Cancer Genome Atlas and found that lower expressions of
vitamin D activity correlate with poorer patient outcomes.
Additionally, an analysis of over one thousand patients treated with
checkpoint inhibitors associated lower vitamin D availability in
tissues to more rapid cancer progression.
The team also turned to data on a large cohort of Danish participants
who had at least one vitamin D serum measurement before their first
cancer diagnosis. They noted that low vitamin D serum levels correlate
to increased cancer risk over a decade, highlighting vitamin D as a
prospective risk factor for human cancer development.
## **Future Implications**
Checkpoint inhibitors, while a remarkable advance in cancer care,
deliver varying results. For some patients, they evoke durable
responses; for others, no responses at all. While further study is
needed to determine the exact mechanism at hand, this study points to
vitamin D as a possible solution. If the link between this nutrient
and antitumor responses remains true in humans, cancer patients
undergoing checkpoint inhibitor therapy could increase their vitamin D
intake to improve tumor resistance—a simple diet change with
potentially huge benefits. This study joins a sea of research probing
the potential of microbes to improve checkpoint inhibitor therapy.
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