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Abstracts of the 22
nd
National Congress of Digestive Diseases / Digestive and Liver Disease 48S2 (2016) e67–e231
ratios. Multivariate modeling with prognostic covariates was also
performed.
Results:
For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and
KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with
median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4
and 3DL1 was associated with increased CR rates (OR 3.1). After
univariate analysis, patients that underwent resective surgery of
tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80
showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis
identified as parameters independently related to OS the type of
treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR
for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no
association with KIR/HLA genes was observed. Instead, no significant
differences were noted between KIR gene frequencies in RC patients
compared with normal subjects, but when combinations of KIR genes
and their HLA ligands were considered on the survival of patients,
there were significant increases in frequencies of KIR2DL1 (inhibitory
KIR) and A-Bw4 (ligand for inhibitory KIR3DL1) in recurrence, while
KIR3DS1/HLA-Bw4-I80 and KIR2DS3 reduced the risk of recurrence.
Conclusions:
This study, for the first time, evidences that the
genotyping for KIR-HLA pairs are found predictive markers
associated with complete response and improves overall survival
prediction of FOLFIRI treatment response in metastatic colorectal
cancer. These results suggest a role of the KIR/HLA system in patient
outcome, and guide new research on the immunogenetics of mCRC
through mechanistic studies and clinical validation.
OC.04.3
EXPRESSION OF TBET AND RORGAMMA-T IN REGULATORY T
CELLS INFLUENCE THE INCIDENCE AND SIZE OF TUMOR MASSES
IN A CAC MODEL
Rizzo A.*, Franze’ E., Monteleone G., Fantini M.C.
Universita’ Roma Tor Vergata, Roma, Italy
Background and aim:
Mucosal inflammation drives colon carcino
genesis is not fully understood. Although accumulation of FoxP3-
expressing T regulatory cells (Tregs) in sporadic colorectal cancer
tissue represents a positive prognostic factor, co-expression of
the Th17-related transcription factor ROR-gamma-t and IL17A in
these cells promotes tumor growth. Tregs can also co-express Tbet
and RORgamma-t during chronic inflammation but their role in
the development of colitis-associated colorectal cancer (CAC) is
unknown. In this study, we investigated the functional role of Tbet
and/or ROR-gammat-expressing Tregs in CAC murine model.
Material and methods:
Treg specific Tbet and RORgammat con
ditional knockout (ko) mice were used in a CAC model based on the
initial intraperitoneal injection of AOM followed by 3 cycles of 7 days
administration of oral 2% DSS each separated by 14 days in which
mice were kept on water. Colitis severity and tumor onset were
assessed by endoscopy and mice were killed at day 80. Expression of
pro and anti-inflammatory proteins was assessed in the tumoral and
pertumoral tissue of mice by RT-PCR and IHC. The expression of TF
and cytokines Th1 and Th-17-related were analyzed in the Tregs and
conventional non-Treg (ConvT) cells by flow cytometry.
Results:
At the end of the AOM/DSS protocol, wt mice developed
multiple polyps in the context of the inflamed mucosa. Although
Tbet ko mice showed milder colitis during the first DSS cycle as
compared to theWt, this difference was lost at end of the experiment
where tumor incidence and mean size resulted similar between the
groups. In contrast, the colon of RORgamma-t ko mice resulted more
inflamed as compared to Wt but characterized by fewer and smaller
tumors. The accumulation of FoxP3-expressing Tregs and ConvT
cells did not differ in the peritumotal and tumoral areas among the
groups. However, depletion RORgammat in Tregs caused a reduced
expression of IL-6 and STAT3 phosphorylation in epithelial cells.
Conclusions:
In a CAC model RORgamma-t but not Tbet expression by
Tregs promotes severe colitis characterized by low expression of IL6.
At the same time these mice develop a reduced number of tumors of
small size characterized by a low expression of p-STAT3 thus implying
that the expression of ROR-gammat in Tregs is required to sustain the
IL-6-STAT3 carcinogenetic axis operating in the CAC.
OC.04.4
FROM INFLAMMATORY BOWEL DISEASE TO COLON CANCER:
WHAT IS THE ROLE OF INFILTRATING IMMUNE CELLS?
Lo Presti E.*
1
, Di Mitri R.
2
, Dieli F.
1
, Mocciaro F.
2
, Pecoraro G.M.
2
,
Russo G.
2
, Meraviglia S.
1
1
Dipartimento di Biopatologia e Metodologie Biomediche, University
of Palermo; Central Laboratory of Advanced Diagnosis and Biomedical
Research (CLADIBIOR), University of Palermo., Palermo, Italy,
2
U.O.C.
di Gastroenterologia ed Endoscopia Digestiva, A.R.N.A.S. Civico-Di
Cristina-Benfratelli, Palermo, Italy
Background and aim:
Patients with ulcerative colitis and Crohn’s
disease have an increased risk of developing colorectal cancer
(CRC) but the underlying mechanisms are unknown. Several studies
have demonstrated that colitis-associated CRC (CAC) is more
aggressive compared to sporadic CRC, suggesting a role for the host
inflammatory response. The aim of our study is to understand if and
how chronic inflammation contributes to the development of CRC.
Material and methods:
Immune cells were isolated from fresh
intestinal biopsy tissues. This pilot study collected 30 samples of
which IBD at onset (n=8), IBD after therapy (n=7), CRC (n=9), CAC
(n=2) and healthy donors (n=4). The samples was digested and after
were stained with fluorochrome conjugated monoclonal antibodies
against intracellular and surface markers to identify specific
lymphocyte subsets. Acquisition was performed on a FACS Canto II
flow cytometer and data were analysed with FlowJo.
Results:
IBD patients both at onset and after therapy, showed a
different pattern of infiltrating immune cells compared to CRC
and CAC, not only in terms of frequency but also of cytokine
production. Accordingly, the frequency of type-1 innate lymphoid
cells (ILC1) was higher in IBD (mean around 20%), compared to CAC
and sporadic CRC; moreover, these infiltrating ILC1 produced high
amounts of TNF-
a
in beginning IBD patients at onset, compared to
treated IBD and sporadic CRC. We also observed higher frequencies
of infiltrating V
d
1 in CRC
compared to IBD at onset, while V
d
2 cells had an opposite pattern.
The cytokine production analysis revealed that V
d
1 T cells produced
IL-17 in sporadic CRC and IFN-
g
in IBD, while V
d
2 T cells produce
IL-17 only in treated IBD patients and did not show any differences
for IFN-
g
production. TNF-
a
was produced exclusively by V
d
2 T cells
without significative differences in all tested group.
Conclusions:
Our preliminary results suggest an appreciated and
unexpected role for distinct subsets of innate lymphoid cells in
the progression from colitis to colon cancer and provides a tool to
evaluate their contribution to the development of cancer-associated
chronic inflammation.
OC.04.5
RECURRENCE AFTER ENDOSCOPIC RESECTION OF ADVANCED
COLORECTAL ADENOMA: A RECURSIVE PARTITIONING ANALYSIS
OF PREDICTIVE FACTORS
Facciorusso A.
1
, Di Maso M.*
1
, Serviddio G.
1
, Vendemiale G.
1
,
Spada C.
2
, Costamagna G.
2
, Muscatiello N.
1
1
University of Foggia, Foggia, Italy,
2
Catholic University, Rome, Italy
Background and aim:
Several studies have pointed out different
risk factors for advanced colorectal adenoma (ACA) recurrence