Gut Microbes May Shape Response to Cancer Immunotherapy
New studies indicate that
the composition of gut bacteria can influence the effectiveness of certain
cancer immunotherapy drugs and that manipulating the gut microbiome may
potentially expand the numbers of patients who benefit from cancer
immunotherapies.
Programmed cell death
protein 1 (PD-1) inhibitors, or so-called immune checkpoint inhibitors, unleash
T lymphocyte–mediated immune responses by suppressing the interaction of T
inhibitory receptors with ligands on tumor cells. They are highly effective against
advanced melanoma, non–small cell lung cancer, and renal cell carcinoma—but
only in a minority of patients. Two recent research studies in Science,
which examined how patients’ gut microbiomes correlate with their cancers’
response to PD-1 inhibitors, suggest that the gut microbiome may in part
account for individual differences in drug efficacy.
Investigators from the
Gustave Roussy Cancer Campus in France and their colleagues explored how
antibiotics, which can transiently change the composition of the gut
microbiome, might affect the outcomes of patients receiving PD-1 inhibitors for
the treatment of lung, kidney, or urothelial cancer. In the study. patients who
had taken antibiotics for other conditions within 2 months before or 1 month
after the first administration of anti–PD-1 therapy had reduced
progression-free and overall survival compared with patients who had not taken
antibiotics during that time.
The investigators also
found that an abundance of the bacterium Akkermansia muciniphila in the
gut was associated with the best clinical response to treatment. The species
was detectable in 69% and 58% of patients exhibiting a partial response or
stable disease, respectively, but only in 34% of patients who progressed or
died. In support of these findings, in mice treated with antibiotics, fecal
transplants from patients whose cancers responded to anti–PD-1 therapy improved
the effectiveness of the therapy after a subsequent tumor challenge. Scientists
suspect that the cytokine IL-12, which is released in response to A
muciniphila, may help rally T cells to combat cancer.
In a separate study, a
team led by researchers at the University of Texas MD Anderson Cancer Center in
Houston found that patients whose melanoma responded better to PD-1 inhibitors
had greater gut microbe diversity. Furthermore, patients whose microbiomes were
enriched with bacteria in the Faecalibacterium genus and the
Clostridiales order were more likely to respond to treatment and to experience
longer progression-free survival compared with patients whose microbiomes were
more enriched with bacteria of the Bacteroidales order.
The former patients
tended to have more CD8+ T cells, with enhanced systemic and antitumor
immunity, whereas the latter had higher levels of circulating regulatory T
cells, myeloid-derived suppressor cells, and a blunted cytokine response,
resulting in dampening of antitumor immunity. In addition, a favorable
microbiome was associated with increased antigen processing and presentation by
immune cells at cancer sites.
“Though some data were available linking
diversity and composition of the gut microbiome to other forms of cancer
treatment, these papers are the first to demonstrate that diversity and
signatures within the gut microbiome may modulate responses to immune
checkpoint blockade in patients across cancer types.
Additional research is needed to uncover
the precise mechanisms by which bacterial strains exert such profound
immunomodulatory effects in the body. The studies’ results also raise a number
of questions: should physicians profile the gut microbiome of patients before
initiating immunotherapy, and should these patients avoid the use of
antibiotics or certain foods that might have a detrimental effect on healthy
gut bacteria? “These questions beg to be answered, and we need to work together
as a global community to answer them.
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