Abstract Book 2010 - CIMT Annual Meeting

101 Karakhanova | Tumor biology & interaction with the immune system
IFN-α up-regulates B7-H1 expression on dendritic cells
and pancreatic tumor cells
Svetlana Karakhanova 1 , Ralf Jesenofsky 2 , Susanne Serba 1 , Alexandr V. Bazhin 1 , Jan Schmidt 1
1 Department of Surgery, University of Heidelberg, Germany
2 II. University Hospital, Mannheim, Germany
150
Pancreatic carcinoma is one of the most aggressive
human malignant tumors and most lethal cancers
worldwide. Despite recent advances in surgery, radiation
and chemotherapy, outcome of pancreatic
cancer could be improved only partially. Therefore
novel approaches are strongly needed. Immunotherapy
represents such an option. Clinical data
show promising results for approaches combining
chemotherapeutics with activating cytokines, like
IFN-α. However, in parallel with immune stimulating
effects of this treatment, the presence and induction
of immunosuppressive mechanisms should
be considered in the course of such a pancreatic
cancer therapy. Regulatory molecules of the B7-H
family, especially B7-H1 (PD-L1, CD274), play an important
role in the regulation of immune responses.
In human pancreatic carcinoma tissue B7-H1 is upregulated
and the patients, demonstrating increased
B7-H1 expression have a poor prognosis. B7-H1
expression in pancreatic tumors contributes to the
tumor immune evasion and tumor progression and,
as recently demonstrated, blocking of B7-H1 improves
anti-tumor effects in a mouse pancreatic cancer
model.
In our study we aim to investigate the expression
and function of B7-H1 molecules in the context of
IFN-α therapy of pancreatic cancer.
Using Flow cytometry, cytological methods as well
as RT-PCR approaches, we showed that B7-H1 expression
is up-regulated on human dendritic cells
(DC) and some human pancreatic cancer cell lines
upon treatment with IFN-α. Interestingly, in some
cell lines we observed additive effect of 5-FU (chemotherapeutic
agents used for pancreatic carcinoma
treatment) and IFN-α on the increase of B7-H1
expression. To confirm the inhibitory potential of
IFN-α -induced B7-H1 molecule, we performed cocultures
of T-Cells and IFN-α-treated DC with and
without blocking of B7-H1 with specific antibodies
and measured proliferation and cytokine production
from T-cells. In ongoing study we are using an
orthotopic mouse model of pancreatic carcinoma to
demonstrate that additional blocking of B7-H1 molecule
during 5-FU and IFN-α combinatory therapy
may additionally improve the outcome of this treatment.
Our data demonstrate that, despite the stimulation
of anti-tumor effects, IFN-α up regulates the expression
of immunosuppressive B7-H1 molecules,
which could limit the effect of immunotherapy
with IFN-α. Thus, it could be of advantage to reduce
undesirable site effects of the IFN-α-induced B7-H1
expression on the tumor and immune cells.