After stratification, the hazard ratio in the group perfused with MMC compared to oxaliplatin was 0.17 (0.06 to 0.45), p < 0.001. Median disease-free survival was higher in the MMC group (37.1 vs 24 months), p ¼ 0.029. There was no difference in received adjuvant chemotherapy (p > 0.05). CONCLUSIONS: These data suggest that HIPEC perfusion with mitomycin C is associated with favorable survival outcomes compared to perfusion with oxaliplatin.
Objectives
Pancreatic ductal adenocarcinoma (
PDAC
) is an aggressive disease with a poor prognosis.
PDAC
has poor response to immunotherapy because of its unique tumour microenvironment (
TME
). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the
TME
to improve immunogenicity.
Methods
In vitro
human
PDAC
cell lines
MiaPaca2
and
S2
‐013 were treated with 5
μ
m
3‐Deazaneplanocin
A (
DZNep
, an
EZH2
inhibitor) and 5
μ
m
5‐Azacytidine
(
5‐AZA
, a
DNMT1
inhibitor).
In vivo
orthotopic murine tumour models using both murine
PAN02
cells and
KPC
cells inoculated in immunocompetent
C56
/
BL7
mice were treated with
anti‐PD‐L1
combined with
DZNep
and
5‐AZA
. Short hairpin knockdown (
KD
) of
EZH2
and
DNMT1
in
PAN02
cells for the orthotopic murine tumour model was established to validate the drug treatment (
DZNep
and
5‐AZA
).
qRT‐PCR
and microarray assays were performed for the evaluation of Th1‐attracting chemokines and cancer‐associated antigen induction.
Results
Drug treatments induced significant upregulation of gene expressions of Th1‐attracting chemokines,
CXCL9
and
CXCL10
, and the cancer–testis antigens,
NY‐ESO‐1
,
LAGE
and
SSX‐4
(
P
< 0.05). In orthotopic tumour models, inoculation of
PAN02
cells or
KPC
cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic
Pan02‐KD
model, the
anti‐PD‐L1
treatment also caused significant tumour regression.
Conclusion
We demonstrate that immunotherapy for
PDAC
can be potentiated with epigenetic therapy by increasing cancer‐associated antigen expression and increased T‐cell trafficking across the immunosuppressive tumour microenvironment via upre...
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