Acta Neuropathologica Communications,
Год журнала:
2024,
Номер
12(1)
Опубликована: Апрель 8, 2024
Abstract
In
malignant
glioma,
cytotoxic
drugs
are
often
inhibited
from
accessing
the
tumor
site
due
to
blood-tumor
barrier
(BTB).
Ibrutinib,
FDA-approved
lymphoma
agent,
inhibits
Bruton
tyrosine
kinase
(BTK)
and
has
previously
been
shown
independently
impair
aortic
endothelial
adhesion
increase
rodent
glioma
model
survival
in
combination
with
therapy.
Yet
additional
research
is
required
understand
ibrutinib’s
effect
on
BTB
function.
this
study,
we
detail
baseline
BTK
expression
cells
its
surrounding
vasculature,
then
measure
junctional
expression/function
changes
varied
ibrutinib
doses
vitro.
Rat
models
were
treated
alone
(1–10
µM
25
mg/kg)
doxil
(10–100
3
assess
additive
effects
viability,
drug
concentrations,
volume,
survival.
We
found
that
ibrutinib,
a
dose-dependent
manner,
decreased
brain
cell–cell
over
24
h,
without
affecting
cell
viability
(
p
<
0.005).
Expression
of
tight
junction
gene
protein
was
maximally
4
h
after
administration,
along
inhibition
efflux
transporter,
ABCB1,
activity.
demonstrated
an
rat
cells,
as
seen
by
significant
reduction
0.001)
increased
CNS
concentration
(56
ng/mL
vs.
74.6
combination,
0.05).
Finally,
combined
doxil,
prolonged
median
(27
16
days,
0.0001)
imaging
showing
−
53%
versus
75%
volume
change
therapy
These
findings
indicate
ability
permeability
via
disruption
inhibition,
entry
prolong
Our
results
motivate
need
identify
other
modifiers,
all
intent
improving
reducing
systemic
toxicities.
Journal of Hematology & Oncology,
Год журнала:
2024,
Номер
17(1)
Опубликована: Май 8, 2024
Abstract
Glioblastoma
(GBM),
the
predominant
and
primary
malignant
intracranial
tumor,
poses
a
formidable
challenge
due
to
its
immunosuppressive
microenvironment,
thereby
confounding
conventional
therapeutic
interventions.
Despite
established
treatment
regimen
comprising
surgical
intervention,
radiotherapy,
temozolomide
administration,
exploration
of
emerging
modalities
such
as
immunotherapy
integration
medicine
engineering
technology
therapy,
efficacy
these
approaches
remains
constrained,
resulting
in
suboptimal
prognostic
outcomes.
In
recent
years,
intensive
scrutiny
inhibitory
milieu
within
GBM
has
underscored
significance
cellular
constituents
microenvironment
their
interactions
with
cells
neurons.
Novel
immune
targeted
therapy
strategies
have
emerged,
offering
promising
avenues
for
advancing
treatment.
One
pivotal
mechanism
orchestrating
immunosuppression
involves
aggregation
myeloid-derived
suppressor
(MDSCs),
glioma-associated
macrophage/microglia
(GAM),
regulatory
T
(Tregs).
Among
these,
MDSCs,
though
constituting
minority
(4–8%)
CD45
+
GBM,
play
central
component
fostering
evasion
propelling
tumor
progression,
angiogenesis,
invasion,
metastasis.
MDSCs
deploy
intricate
mechanisms
that
adapt
dynamic
(TME).
Understanding
interplay
between
provides
compelling
basis
This
review
seeks
elucidate
inherent
explore
existing
targets,
consolidate
insights
into
MDSC
induction
contribution
immunosuppression.
Additionally,
comprehensively
surveys
ongoing
clinical
trials
potential
strategies,
envisioning
future
where
targeting
could
reshape
landscape
GBM.
Through
synergistic
other
modalities,
this
approach
can
establish
multidisciplinary,
multi-target
paradigm,
ultimately
improving
prognosis
quality
life
patients
Cellular and Molecular Immunology,
Год журнала:
2024,
Номер
21(12), С. 1354 - 1375
Опубликована: Окт. 15, 2024
Glioblastoma
(GBM)
is
an
aggressive
and
lethal
type
of
brain
tumor
in
human
adults.
The
standard
care
offers
minimal
clinical
benefit,
most
GBM
patients
experience
recurrence
after
treatment.
In
recent
years,
significant
advancements
have
been
made
the
development
novel
immunotherapies
or
other
therapeutic
strategies
that
can
overcome
immunotherapy
resistance
many
advanced
cancers.
However,
benefit
immune-based
treatments
limited
because
unique
immune
profiles,
cell
heterogeneity,
immunosuppressive
microenvironment.
this
review,
we
present
a
detailed
overview
current
immunotherapeutic
discuss
challenges
potential
molecular
mechanisms
underlying
GBM.
Furthermore,
provide
in-depth
discussion
regarding
GBM,
which
will
likely
require
combination
therapies.
Cell Reports Medicine,
Год журнала:
2023,
Номер
4(11), С. 101238 - 101238
Опубликована: Окт. 18, 2023
Glioblastoma
(GBM)
is
a
hypoxic
and
"immune-cold"
tumor
containing
rich
stromal
signaling
molecules
cell
populations,
such
as
proteases
immunosuppressive
tumor-associated
macrophages
(TAMs).
Here,
we
seek
to
profile
characterize
the
potential
that
may
contribute
GBM
immunosuppression.
Legumain
(LGMN)
emerges
key
protease
highly
enriched
in
TAMs
transcriptionally
upregulated
by
hypoxia-inducible
factor
1-alpha
(HIF1α).
Functionally,
increased
LGMN
promotes
TAM
polarization
via
activating
GSK-3β-STAT3
pathway.
Inhibition
of
macrophage
HIF1α
reduces
polarization,
impairs
progression,
enhances
CD8+
T
cell-mediated
anti-tumor
immunity,
synergizes
with
anti-PD1
therapy
mouse
models.
Thus,
molecular
switch
connecting
two
hallmarks
hypoxia
immunosuppression,
providing
an
actionable
therapeutic
intervention
for
this
deadly
disease.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Фев. 7, 2024
Abstract
Melanoma
incidence
and
mortality
rates
are
historically
higher
for
men
than
women.
Although
emerging
studies
have
highlighted
tumorigenic
roles
the
male
sex
hormone
androgen
its
receptor
(AR)
in
melanoma,
cellular
molecular
mechanisms
underlying
these
sex-associated
discrepancies
poorly
defined.
Here,
we
delineate
a
previously
undisclosed
mechanism
by
which
androgen-activated
AR
transcriptionally
upregulates
fucosyltransferase
4
(
FUT4
)
expression,
drives
melanoma
invasiveness
interfering
with
adherens
junctions
(AJs).
Global
phosphoproteomic
fucoproteomic
profiling,
coupled
vitro
vivo
functional
validation,
further
reveal
that
AR-induced
fucosylates
L1
cell
adhesion
molecule
(L1CAM),
is
required
FUT4-increased
metastatic
capacity.
Tumor
microarray
gene
expression
analyses
demonstrate
AR-FUT4-L1CAM-AJs
signaling
correlates
pathological
staging
patients.
By
delineating
key
androgen-triggered
enhances
aggressiveness,
our
findings
help
explain
clinical
outcome
disparities
highlight
AR/FUT4
effectors
as
potential
prognostic
biomarkers
therapeutic
targets
melanoma.
Neuro-Oncology,
Год журнала:
2024,
Номер
26(7), С. 1213 - 1227
Опубликована: Фев. 27, 2024
Glioblastoma
(GBM)
is
a
highly
malignant
brain
tumor
that
affects
men
more
often
than
women.
In
addition,
the
former
shows
poorer
survival
prognosis.
To
date,
reason
for
this
sex-specific
aggressiveness
remains
unclear.
Therefore,
aim
of
study
to
investigate
processes
explain
these
sex
differences.
Cancer Discovery,
Год журнала:
2024,
Номер
14(6), С. 1106 - 1131
Опубликована: Фев. 27, 2024
Recent
clinical
trials
have
highlighted
the
limited
efficacy
of
T
cell-based
immunotherapy
in
patients
with
glioblastoma
(GBM).
To
better
understand
characteristics
tumor-infiltrating
lymphocytes
(TIL)
GBM,
we
performed
cellular
indexing
transcriptomes
and
epitopes
by
sequencing
single-cell
RNA
paired
V(D)J
sequencing,
respectively,
on
TILs
from
two
cohorts
totaling
15
high-grade
glioma,
including
GBM
or
astrocytoma,
IDH-mutant,
grade
4
(G4A).
Analysis
CD8+
TIL
landscape
reveals
an
enrichment
clonally
expanded
GZMK+
effector
cells
tumor
compared
matched
blood,
which
was
validated
at
protein
level.
Furthermore,
integration
other
cancer
types
highlights
lack
a
canonically
exhausted
T-cell
population
TIL.
These
data
suggest
that
represent
important
subset
within
microenvironment
may
harbor
potential
therapeutic
implications.
