Abstract Book 2010 - CIMT Annual Meeting

091 Ramacher | Tumor biology & interaction with the immune system
Immunosuppression in transgenic mouse melanoma
model induced by myeloid derived suppressor cells
Marcel Ramacher 1 , Michal Baniyash 2 and Viktor Umansky 1
1 German Cancer Research Center (DKFZ), Heidelberg Germany
2 Lautenberg Center for General and Tumor Immunology, Jerusalem, Israel
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Melanoma is known for its poor response to current
immunotherapies due to immunosuppressive cells
in the tumor microenvironment like myeloid derived
suppressor cells (MDSC). We performed the studies
on the ret transgenic mouse model of malignant
melanoma, which resembles human melanoma as
regards to histopathology and clinical development.
After a short latency, 25% of mice develop melanoma
metastasizing to lymph nodes, lungs and liver.
We found that MDSC from tumor bearing mice were
characterized by increased numbers and higher
nitric oxide (NO) production and arginase-1 (ARG1)
expression than those from tumor free mice or nontransgenic
littermates. This phenomenon could be
due to exosomes released by melanoma cells in
vivo. In fact, upon treatment of non-transgenic littermates
with melanoma derived exosomes, MDSC
amounts were significantly elevated.
To investigate the effect of NO and reactive oxygen
species produced by MDSC on CD4+CD25- conventional
(helper) T cells and CD4+CD25+ regulatory
T cells (Treg), these subsets were separated from
spleens and treated with NO donor DETA-NONOate
or hydrogen peroxide in vitro. Both factors induced
much higher apoptosis in conventional T cells than
in Tregs suggesting thereby the Treg resistance
to the immunosuppressive microenvironment. To
reduce the MDSC immunosuppressive effect and
to improve antitumor immune responses, tumor
bearing mice were treated orally with an inhibitor
of phosphodiesterase (PDE)-5 sildenafil (Viagra).
Lower NO production and ARG1 expression in
MDSC was correlated with the inhibition of melanoma
progression. We suggest that an effective
immunotherapy should include the inhibition of
MDSC immunosuppressive functions.