Abstracts for the 25th Annual Scientific Meeting of the International ...

J Immunother Volume 33, Number 8, October 2010
Abstracts
Our observations are consistent with the notion that Treg have an
anti-inflammatory and protective role in CRC, however this role is
compromised by their interaction with MC in the course of
progressive disease. Thus, the cross talk between MC and Treg
determines the level of inflammation in CRC. The shift of Treg to a
pro-inflammatory phenotype is a turning point in the escalation of
cancer-associated inflammation 1,2 (see commentary 3 ).Basedonthese
observations we propose that MC and their interaction with Treg are
suitable targets for effective therapeutic intervention in CRC.
References:
1. Blatner NR, Bonertz A, Beckhove P, et al. In colorectal cancer
mast cells contribute to systemic regulatory T-cell dysfunction.
Proc Natl Acad Sci USA. 2010.
2. Gounaris E, Blatner NR, Dennis K, et al. T-regulatory cells shift
from a protective anti-inflammatory to a cancer-promoting proinflammatory
phenotype in polyposis. Cancer Res. 2009;69:5490–5497.
3. Colombo MP, Piconese S. Polyps wrap mast cells and treg
within tumorigenic tentacles. Cancer Res. 2009.
Roles of Interleukin-4 Receptor a-chain on Glioma-Infiltrating
Monocytes
Gary Kohanbash*, Arlan H. Mintz*, Kayla McKaveney*, Heather
A. McDonald*, John R. Ohlfestw, Hideho Okada*, Mitsugu
Fujita*. *University of Pittsburgh, Pittsburgh, PA; w University of
Minnesota, Minneapolis, MN.
Several epidemiological studies have indicated association of single
nucleotide polymorphisms and haplotypes in the IL-4Ra gene with
altered glioma risk and prognosis. IL-4Ra is expressed on
immunosuppressive cells of monocyte lineage and mediates their
production of transforming growth factor (TGF)-b in response to IL-
4 or IL-13. In this regard, our evaluation of tumor-infiltrating
leukocytes in human malignant gliomas (n = 7) revealed that gliomainfiltrating
CD14 + monocytes express high levels of IL-4Ra. By
contrast, CD14 + monocytes in peripheral blood expressed barely
detectable levels of IL-4Ra, suggesting the unique up-regulation of
IL-4Ra in the glioma microenvironment. Based on these observations,
we sought to address the functional significance of IL-4Ra in a
recently developed murine de novo glioma model. We induced de
novo gliomas in BALB/c-background mice by intracerebroventricular
transfection of oncogenes using the Sleeping Beauty transposon
system. IL-4Ra-deficient (Il4ra / ) mice exhibited significantly
prolonged symptom-free survival compared with WT mice; median
survival was 89 and 55.5 days, respectively. Consistently, gliomas
induced in the WT mice were infiltrated with significantly higher
numbers of CD11b + Gr1+ immunosuppressive monocytes than
those in the Il4ra / mice. We subsequently isolated gliomainfiltrating
CD11b + Gr1+ monocytes to address their functions. RT-
PCR and ELISA revealed that the monocytes derived from WT mice
express significantly higher levels of TGF-b. SinceTGF-b is known
to inhibit the function of effector T cells, we addressed the
significance of T cells in glioma development by inducing gliomas
in Rag1-deficient (Rag1 / ) mice, which lack adaptive immune
cells including T cells. Rag1 / mice exhibited significantly
shortened survival compared with WT mice. Taken together, these
data suggest that IL-4Ra expression on glioma-infiltrating monocytes
may promote the immunosuppressive microenvironment of gliomas
through a variety of mechanisms including TGF-b production and T
cell inhibition, thereby facilitating glioma growth.
Myeloid-derived Suppressor Cells and Decreased Interferon
Responsiveness in Tumor-Bearing Mice
Bethany L. Mundy*, Gregory Lesinskiw, Kristen Benningerz,
Mahmood Khanz, Periannan Kuppusamyz, Kristan Guenterbergw,
Sri Vidya Kondadasulaz, Abhik Ray Chaudhuryz, Melanie Kreinerz,
Gregory Youngz, DenisGuttridgez, William E. Carsony. *Integrated
Biomedical Sciences; w Internal Medicine; ySurgery, The Ohio State
University; zThe Ohio State University, Columbus, OH.
Our group and others have determined that immune effector cells
from patients with advanced cancers exhibit reduced activation of
IFN induced signaling pathways although the mechanisms underlying
this observation have not been delineated. We hypothesized
that increases in myeloid-derived suppressor cells (MDSC), which
are known to be elevated in the setting of advanced cancers, could
interfere with the host immune response to tumors by inhibiting
immune cell responsiveness to interferons. The C26 murine
adenocarcinoma model was employed to study immune function
in advanced malignancy. This model can mimic advanced disease
in humans by the development of cancer cachexia which is
associated with weight loss, aggressive tumor growth, and elevated
levels of IL-6. Splenocytes from tumor-bearing mice exhibited
reduced phosphorylation of STAT1 (P-STAT1) on Tyr 701
(P