International Journal of Nanomedicine,
Год журнала:
2024,
Номер
Volume 19, С. 507 - 526
Опубликована: Янв. 1, 2024
Introduction:
Chemotherapy
is
still
the
treatment
of
choice
for
advanced
triple-negative
breast
cancer.
combined
with
immunotherapy
being
tried
in
patients
As
a
kind
"cold
tumor",
cancer
has
bottleneck
immunotherapy.
Indoleamine
2,
3-dioxygenase-1
inhibitors
can
reverse
immunosuppressive
state
and
enhance
immune
response.
Methods:
In
this
study,
mesoporous
silica
nanoparticles
were
coated
chemotherapeutic
drug
doxorubicin
indoleamine
3-dioxygenase
1
inhibitor
1-Methyl-DL-tryptophan
(1-MT),
then
encapsulate
surfaces
cell
membrane
to
construct
tumor
dual-targeted
delivery
system
CDIMSN
chemotherapy
immunotherapy,
investigate
immunogenic
death
effect
CDIMSN.
Results
discussion:
The
could
target
microenvironment.
Doxorubicin
induced
death,
while
1-MT
reversed
immunosuppression.
vivo
findings
showed
that
size
group
was
2.66-fold
1.56-fold
smaller
than
DOX
DIMSN
groups,
respectively.
better
naked
stimulating
CD8
+
T
cells,
CD4
cells
promoting
Dendritic
Cells(DC)
maturation.
addition,
blood
analysis,
biochemical
analysis
Hematoxylin
staining
mice
bionic
had
good
biological
safety.
Keywords:
doxorubicin,
nanoparticle,
IDO1
inhibitor,
Cancer & Metabolism,
Год журнала:
2023,
Номер
11(1)
Опубликована: Май 24, 2023
Abstract
Background
The
impact
of
non-small
cell
lung
cancer
(NSCLC)
metabolism
on
the
immune
microenvironment
is
not
well
understood
within
platinum
resistance.
We
have
identified
crucial
metabolic
differences
between
cisplatin-resistant
(CR)
and
cisplatin-sensitive
(CS)
NSCLC
cells
with
elevated
indoleamine
2,3-dioxygenase-1
(IDO1)
activity
in
CR,
recognized
by
increased
kynurenine
(KYN)
production.
Methods
Co-culture,
syngeneic,
humanize
mice
models
were
utilized.
C57BL/6
inoculated
either
Lewis
carcinoma
mouse
(LLC)
or
their
platinum-resistant
counterpart
(LLC-CR)
cells.
Humanized
A
(human
CS
cells)
ALC
CR
cells).
Mice
treated
IDO1
inhibitor
TDO2
(tryptophan
2,3-dioxygenase-2)
at
200
mg/kg
P.O.
once
a
day
for
15
days;
new-in-class,
IDO1/TDO2
dual
AT-0174
170
days
without
anti-PD1
antibody
(10
mg/kg,
every
3
days).
Immune
profiles
KYN
tryptophan
(TRP)
production
evaluated.
Results
tumors
exhibited
more
highly
immunosuppressive
environment
that
debilitated
robust
anti-tumor
responses.
IDO1-mediated
from
suppressed
NKG2D
effector
natural
killer
(NK)
CD8
+
T
enhanced
populations
regulatory
(Tregs)
myeloid-derived
suppressor
(MDSCs).
Importantly,
while
selective
inhibition
attenuated
tumor
growth,
it
concomitantly
upregulated
enzyme.
To
overcome
compensatory
induction
activity,
we
employed
inhibitor,
AT-0174.
Dual
growth
to
greater
degree
than
alone.
Significant
enhancement
frequency
NK
reduction
Tregs
MDSCs
observed
following
AT-1074
treatment.
PD-L1
(programmed
death-ligand-1)
expression
was
cells;
therefore,
assessed
PD1
death
protein-1)
blocking
report
profound
improved
immunity
which
turn
extended
overall
survival
mice.
Conclusion
Our
study
reports
presence
utilize
both
enzymes
survival,
escape
surveillance
as
consequence
metabolites.
also
early
vivo
data
support
potential
therapeutic
efficacy
part
immuno-therapeutic
treatment
disrupts
enhances
immunity.
Malignant
tumors
often
escape
anticancer
immune
surveillance
by
suppressing
the
cytotoxic
functions
of
T
lymphocytes.
While
many
these
evasion
networks
include
checkpoint
proteins,
small
molecular
weight
compounds,
such
as
amino
acid
L-kynurenine
(LKU),
could
also
substantially
contribute
to
suppression
anti-cancer
immunity.
However,
biochemical
mechanisms
underlying
suppressive
effects
LKU
on
T-cells
remain
unclear.
Here,
we
report
for
first
time
that
suppresses
cell
function
an
aryl
hydrocarbon
receptor
(AhR)
ligand.
The
presence
in
cells
is
associated
with
AhR
activation,
which
results
competition
between
and
hypoxia-inducible
factor
1
alpha
(HIF-1α)
nuclear
translocator,
ARNT,
leading
exhaustion.
expression
indoleamine
2,3-dioxygenase
(IDO1,
enzyme
leads
generation)
induced
TGF-β-Smad-3
pathway.
We
show
IDO-negative
cancers
utilize
alternative
route
production
via
endogenous
inflammatory
mediator,
high
mobility
group
box
(HMGB-1)-interferon-gamma
(IFN-γ)
axis.
In
addition,
other
(like
T-cell
lymphomas)
trigger
IDO1
activation
eosinophils
present
tumor
microenvironment
(TME).
These
suppress
function,
thus
support
machinery.
International Journal of Nanomedicine,
Год журнала:
2024,
Номер
Volume 19, С. 507 - 526
Опубликована: Янв. 1, 2024
Introduction:
Chemotherapy
is
still
the
treatment
of
choice
for
advanced
triple-negative
breast
cancer.
combined
with
immunotherapy
being
tried
in
patients
As
a
kind
"cold
tumor",
cancer
has
bottleneck
immunotherapy.
Indoleamine
2,
3-dioxygenase-1
inhibitors
can
reverse
immunosuppressive
state
and
enhance
immune
response.
Methods:
In
this
study,
mesoporous
silica
nanoparticles
were
coated
chemotherapeutic
drug
doxorubicin
indoleamine
3-dioxygenase
1
inhibitor
1-Methyl-DL-tryptophan
(1-MT),
then
encapsulate
surfaces
cell
membrane
to
construct
tumor
dual-targeted
delivery
system
CDIMSN
chemotherapy
immunotherapy,
investigate
immunogenic
death
effect
CDIMSN.
Results
discussion:
The
could
target
microenvironment.
Doxorubicin
induced
death,
while
1-MT
reversed
immunosuppression.
vivo
findings
showed
that
size
group
was
2.66-fold
1.56-fold
smaller
than
DOX
DIMSN
groups,
respectively.
better
naked
stimulating
CD8
+
T
cells,
CD4
cells
promoting
Dendritic
Cells(DC)
maturation.
addition,
blood
analysis,
biochemical
analysis
Hematoxylin
staining
mice
bionic
had
good
biological
safety.
Keywords:
doxorubicin,
nanoparticle,
IDO1
inhibitor,
