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2017 ; 6
(6
): e1316437
Nephropedia Template TP
gab.com Text
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English Wikipedia
Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model
independently of the immunomodulatory and anti-metastatic effects of VEGFR-2
blockade
#MMPMID28680747
Secondini C
; Coquoz O
; Spagnuolo L
; Spinetti T
; Peyvandi S
; Ciarloni L
; Botta F
; Bourquin C
; Rüegg C
Oncoimmunology
2017[]; 6
(6
): e1316437
PMID28680747
show ga
Tumor angiogenesis promotes tumor growth and metastasis. Anti-angiogenic therapy
in combination with chemotherapy is used for the treatment of metastatic cancers,
including breast cancer but therapeutic benefits are limited. Mobilization and
accumulation of myeloid-derived suppressor cells (MDSC) during tumor progression
and therapy have been implicated in metastasis formation and resistance to
anti-angiogenic treatments. Here, we used the 4T1 orthotopic syngenic mouse model
of mammary adenocarcinoma to investigate the effect of VEGF/VEGFR-2 axis
inhibition on lung metastasis, MDSC and regulatory T cells (Tregs). We show that
treatment with the anti-VEGFR-2 blocking antibody DC101 inhibits primary tumor
growth, angiogenesis and lung metastasis. DC101 treatment had no effect on MDSC
mobilization, but partially attenuated the inhibitory effect of mMDSC on T cell
proliferation and decreased the frequency of Tregs in primary tumors and lung
metastases. Strikingly, DC101 treatment induced the expression of the
immune-suppressive molecule arginase I in mMDSC. Treatment with the arginase
inhibitor N(?)-hydroxy-nor-Arginine (Nor-NOHA) reduced the inhibitory effect of
MDSC on T cell proliferation and inhibited number and size of lung metastasis but
had little or no additional effects in combination with DC101. In conclusion,
DC101 treatment suppresses 4T1 tumor growth and metastasis, partially reverses
the inhibitory effect of mMDSC on T cell proliferation, decreases Tregs in tumors
and increases arginase I expression in mMDSC. Arginase inhibition suppresses lung
metastasis independently of DC101 effects. These observations contribute to the
further characterization of the immunomodulatory effect of anti-VEGF/VEGFR2
therapy and provide a rationale to pursue arginase inhibition as potential
anti-metastatic therapy.