Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(39)
Опубликована: Сен. 18, 2023
Although
tumor-intrinsic
fatty
acid
β-oxidation
(FAO)
is
implicated
in
multiple
aspects
of
tumorigenesis
and
progression,
the
impact
this
metabolic
pathway
on
cancer
cell
susceptibility
to
immunotherapy
remains
unknown.
Here,
we
report
that
cytotoxicity
killer
T
cells
induces
activation
FAO
upregulation
carnitine
palmitoyltransferase
1A
(CPT1A),
rate-limiting
enzyme
cells.
The
repression
CPT1A
activity
or
expression
renders
more
susceptible
destruction
by
cytotoxic
lymphocytes.
Our
mechanistic
studies
reveal
deficiency
abrogates
prosurvival
signaling
under
immune
cytolytic
stress.
Furthermore,
identify
cell–derived
IFN-γ
as
a
major
factor
responsible
for
induction
an
AMPK-dependent
manner,
indicating
dynamic
interplay
between
effector
tumor
targets.
While
growth
absence
largely
unaffected,
established
tumors
upon
inhibition
become
significantly
responsive
cellular
immunotherapies
including
chimeric
antigen
receptor-engineered
human
Together,
these
findings
uncover
mode
resistance
editing
can
facilitate
escape
limit
benefits
immunotherapies.
Cell Metabolism,
Год журнала:
2023,
Номер
35(4), С. 633 - 650.e9
Опубликована: Март 9, 2023
The
metabolic
state
represents
a
major
hurdle
for
an
effective
adoptive
T
cell
therapy
(ACT).
Indeed,
specific
lipids
can
harm
CD8+
(CTL)
mitochondrial
integrity,
leading
to
defective
antitumor
responses.
However,
the
extent
which
affect
CTL
functions
and
fate
remains
unexplored.
Here,
we
show
that
linoleic
acid
(LA)
is
positive
regulator
of
activity
by
improving
fitness,
preventing
exhaustion,
stimulating
memory-like
phenotype
with
superior
effector
functions.
We
report
LA
treatment
enhances
formation
ER-mitochondria
contacts
(MERC),
in
turn
promotes
calcium
(Ca2+)
signaling,
energetics,
As
direct
consequence,
potency
LA-instructed
CD8
cells
vitro
vivo.
thus
propose
as
ACT
potentiator
tumor
therapy.
Science,
Год журнала:
2022,
Номер
378(6622), С. 853 - 858
Опубликована: Ноя. 24, 2022
Immune
cells
are
being
engineered
to
recognize
and
respond
disease
states,
acting
as
a
"living
drug"
when
transferred
into
patients.
Therapies
based
on
immune
now
clinical
reality,
with
multiple
T
cell
therapies
approved
for
treatment
of
hematologic
malignancies.
Ongoing
preclinical
studies
testing
diverse
strategies
modify
the
fate
function
applications
in
cancer,
infectious
disease,
beyond.
Here,
we
discuss
current
progress
treating
human
therapeutics,
emerging
engineering,
challenges
facing
field,
particular
emphasis
where
most
effort
has
been
applied
date.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Апрель 26, 2024
The
induced
pluripotent
stem
cell
(iPSC)
technology
has
transformed
in
vitro
research
and
holds
great
promise
to
advance
regenerative
medicine.
iPSCs
have
the
capacity
for
an
almost
unlimited
expansion,
are
amenable
genetic
engineering,
can
be
differentiated
into
most
somatic
types.
been
widely
applied
model
human
development
diseases,
perform
drug
screening,
develop
therapies.
In
this
review,
we
outline
key
developments
iPSC
field
highlight
immense
versatility
of
modeling
therapeutic
applications.
We
begin
by
discussing
pivotal
discoveries
that
revealed
potential
a
nucleus
reprogramming
led
successful
generation
iPSCs.
consider
molecular
mechanisms
dynamics
as
well
numerous
methods
available
induce
pluripotency.
Subsequently,
discuss
various
iPSC-based
cellular
models,
from
mono-cultures
single
type
complex
three-dimensional
organoids,
how
these
models
elucidate
diseases.
use
examples
neurological
disorders,
coronavirus
disease
2019
(COVID-19),
cancer
diversity
disease-specific
phenotypes
modeled
using
iPSC-derived
cells.
also
used
high-throughput
screening
toxicity
studies.
Finally,
process
developing
autologous
allogeneic
therapies
their
alleviate
