A
new study shows two chemotherapy drugs prevalent in the clinic—gemcitabine and
5-fluorouracil—influence the immune response in a way that facilitates tumor
growth. The research, conducted in mice, is published in Nature Medicine.
François Ghiringhelli, MD, PhD, and Lionel
Apetoh, PhD, of the Institut National de la Santé et de la Recherche Médicale
and Centre Georges-François Leclerc in Dijon, France, and colleagues have
uncovered a novel mechanism by which two chemotherapy agents activate the NLRP3
inflammasome complex within myeloid-derived suppressor cells that results in
production of the cytokine interleukin (IL)-1β.
This was shown by the study researchers to
prevent a robust immune response against the tumor.
The experiments also showed that higher IL-1β
levels led to secretion of another cytokine, IL-17, a pro-inflammatory
cytokine, by CD4+ T-cells. The presence of IL-17 limited the antitumor effect
of 5-fluorouracil and enhanced growth of mouse tumors. IL-17 has previously
been shown to promote cancer growth and tumor progression.
“These results unravel the ambivalent effect
of gemcitabine and 5-fluorouracil in the antitumor immune response,” conclude
the authors in the publication.
According to Jeff Weber, MD, PhD, of the Moffitt
Cancer Center in Tampa, Florida, while this study is well done and highlights
the complexity of the potential counteracting effects of frequently used
chemotherapy, there are also limitations. The study focused more on
5-fluorouracil than gemcitabine, and there is only modest human evidence that
confirms the hypothesis.
A concern about the clinical application of
this research, according to Weber, is that 5-fluorouracil is given in along
with leucovorin, which enhances the activity of the chemotherapy, and is often
given in combination with bevacizumab(Drug information on bevacizumab) and
oxaliplatin(Drug information on oxaliplatin), which “may counteract some of the
immune suppressive mechanism noted in [the study],” said Weber.
Whether chemotherapy promotes or prevents the
patient’s immune system from acting on his or her cancer is a subject for
debate. There has been recent evidence showing chemotherapy can systemically
facilitate immunosuppression. However, there is also evidence that certain chemotherapies
enhance an antitumor response by the immune system. The challenge, said
Ghiringhelli, is to dissect the immune effect of different drugs in order to
design better combinations to enhance the immune response.
Weber agrees. “Further studies are necessary,
including expanding work with gemcitabine, to further understand the clinical
implications of this outstanding work.” Because there is evidence that certain
chemotherapies have a positive effect on a patient’s immunity, understanding
which treatments and under which circumstances is crucial.
As a gastrointestinal cancer specialist,
Ghiringhelli sought to understand the effect of these two chemotherapies, which
are effective but never lead to a cure for patients. 5-fluorouracil in
particular is often used to treat metastatic colon cancer. “We believe that it
is important to determine the effect of this treatment on the immune system,
and if it could be combined with immunotherapy to enhance its effect,” said
Ghiringhelli.
The new study suggests ways to bypass the
protumor growth activity of gemcitabine and 5-fluorouracil. Mice in the study
that did not express integral factors of the inflammasome complex, either NLRP3
or CASP1, had a more robust antitumor effect following treatment with either
chemotherapy. While the wild-type mice treated with chemotherapy died by day 30
post-treatment, 30% to 42% of the mutant mice were alive and tumor free at day
60 post-treatment. A recombinant IL-1 antagonist also enhanced the antitumor
response to either chemotherapy agent in mice.
According to Ghiringhelli, this new mechanism
is dependent on the type of chemotherapy, suggesting that those “that target
thymidylate synthetase could mediate this effect.” 5-fluorouracil is an
antimetabolite that inhibits the thymidylate synthetase required for DNA
synthesis.
Chronic inflammation has been previously
linked to cancer initiation and progression, including over-activation of
IL-1β. The differences in the response of the immune system to different
chemotherapies may have to do with the mechanism of the therapy. The authors
cite previous studies which show another type of chemotherapy, anthracycline,
can facilitate an anticancer immune response through activation of acute
inflammation and immunogenic cell death, a specific type of tumor cell death
that results in an immune response.
An increase in IL-1β has also been shown in
colorectal patients treated with 5-fluorouracil, according to the authors. This
hints that combining inhibitors of either the inflammasome or IL-1β with either
gemcitabine or 5-fluorouracil could enhance the antitumor effect. “The
inhibition of this pathway could be useful to enhance the efficacy of this
[chemotherapy],” said Ghiringhelli.
A phase I trial to show if an inhibitor of
IL-1β can reverse the resistance to 5-fluorouracil in patients with metastatic
colon cancer is currently ongoing. “That an IL-1β antagonist, already used in
clinical practice, may improve the effects of existing chemotherapy regimens by
reducing the immune suppression detected in this work, is compelling but
depends on further experiments using drugs like 5-fluorouracil in situations as
they are used in patients,” said Weber.
Anna Azvolinsky, PhD
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