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Reduced inflammation in the tumor microenvironment delays the accumulation of
myeloid-derived suppressor cells and limits tumor progression
#MMPMID17942936
Bunt SK
; Yang L
; Sinha P
; Clements VK
; Leips J
; Ostrand-Rosenberg S
Cancer Res
2007[Oct]; 67
(20
): 10019-26
PMID17942936
show ga
Chronic inflammation is frequently associated with malignant growth and is
thought to promote and enhance tumor progression, although the mechanisms which
regulate this relationship remain elusive. We reported previously that
interleukin (IL)-1beta promoted tumor progression by enhancing the accumulation
of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation
leads to cancer through the production of MDSC which inhibit tumor immunity. If
inflammation-induced MDSC promote tumor progression by blocking antitumor
immunity, then a reduction in inflammation should reduce MDSC levels and delay
tumor progression, whereas an increase in inflammation should increase MDSC
levels and hasten tumor progression. We have tested this hypothesis using the 4T1
mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced
potential for inflammation, and IL-1R antagonist-deficient mice, which have an
increased potential for inflammation. Consistent with our hypothesis,
IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and
metastatic tumor progression. Accumulation of MDSC and tumor progression are
partially restored by IL-6, indicating that IL-6 is a downstream mediator of the
IL-1beta-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R
antagonist-deficient mice promotes the accumulation of MDSC and produces MDSC
with enhanced suppressive activity. These results show that immune suppression by
MDSC and tumor growth are regulated by the inflammatory milieu and support the
hypothesis that the induction of suppressor cells which down-regulate tumor
immunity is one of the mechanisms linking inflammation and cancer.
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