Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: Feb. 6, 2025
Abstract
Pancreatic
ductal
adenocarcinoma
has
a
dismal
prognosis.
A
comprehensive
analysis
of
single-cell
multi-omic
data
from
matched
tumour-infiltrated
CD45+
cells
and
peripheral
blood
in
12
patients,
two
published
datasets,
reveals
complex
immune
infiltrate.
Patients
have
either
myeloid-enriched
or
adaptive-enriched
tumour
microenvironment.
Adaptive
cell-enriched
is
intrinsically
linked
with
highly
distinct
B
T
cell
clonal
selection,
diversification,
differentiation.
Using
TCR
data,
we
see
the
largest
expansions
CD8
effector
memory,
senescent
cells,
activated
regulatory
which
are
induced
within
naïve
cells.
We
identify
pathways
that
potentially
lead
to
suppressive
microenvironment,
including
investigational
targets
TIGIT/PVR
SIRPA/CD47.
Analysis
patients
APACT
clinical
trial
shows
myeloid
enrichment
had
shorter
overall
survival
compared
those
adaptive
enrichment.
Strategies
for
rationale
therapeutic
development
this
disease
include
boosting
responses,
targeting
immunosuppressive
macrophages,
specific
Treg
depletion
approaches.
Nature,
Journal Year:
2022,
Volume and Issue:
611(7934), P. 148 - 154
Published: Sept. 28, 2022
Abstract
Recent
single-cell
studies
of
cancer
in
both
mice
and
humans
have
identified
the
emergence
a
myofibroblast
population
specifically
marked
by
highly
restricted
leucine-rich-repeat-containing
protein
15
(LRRC15)
1–3
.
However,
molecular
signals
that
underlie
development
LRRC15
+
cancer-associated
fibroblasts
(CAFs)
their
direct
impact
on
anti-tumour
immunity
are
uncharacterized.
Here
mouse
models
pancreatic
cancer,
we
provide
vivo
genetic
evidence
TGFβ
receptor
type
2
signalling
healthy
dermatopontin
universal
is
essential
for
myofibroblasts.
This
axis
also
predominantly
drives
fibroblast
lineage
diversity
human
cancers.
Using
newly
developed
Lrrc15–
diphtheria
toxin
knock-in
to
selectively
deplete
CAFs,
show
depletion
this
markedly
reduces
total
tumour
content.
Moreover,
CAF
composition
recalibrated
towards
fibroblasts.
relieves
suppression
tumour-infiltrating
CD8
T
cells
enhance
effector
function
augments
regression
response
anti-PDL1
immune
checkpoint
blockade.
Collectively,
these
findings
demonstrate
TGFβ-dependent
CAFs
dictate
tumour-fibroblast
setpoint
promote
growth.
These
directly
suppress
cell
limit
responsiveness
Development
treatments
restore
homeostatic
reducing
pro-disease
myofibroblasts
may
improve
patient
survival
immunotherapy.
Cancer Cell,
Journal Year:
2023,
Volume and Issue:
41(8), P. 1498 - 1515.e10
Published: July 13, 2023
Type
1
conventional
dendritic
cells
(cDC1)
can
support
T
cell
responses
within
tumors
but
whether
this
determines
protective
versus
ineffective
anti-cancer
immunity
is
poorly
understood.
Here,
we
use
imaging-based
deep
learning
to
identify
intratumoral
cDC1-CD8+
clustering
as
a
unique
feature
of
immunity.
These
clusters
form
selectively
in
stromal
tumor
regions
and
constitute
niches
which
cDC1
activate
TCF1+
stem-like
CD8+
cells.
We
distinct
population
immunostimulatory
CCR7neg
that
produce
CXCL9
promote
cluster
formation
cross-present
antigens
these
niches,
required
for
differentiation
expansion
promotes
cancer
immune
control.
Similarly,
human
cancers,
interact
with
are
associated
patient
survival.
Our
findings
reveal
an
phase
the
response
orchestrated
by
tumor-residing
could
be
exploited
therapy.
Science,
Journal Year:
2023,
Volume and Issue:
379(6633)
Published: Feb. 16, 2023
The
induction
of
proinflammatory
T
cells
by
dendritic
cell
(DC)
subtypes
is
critical
for
antitumor
responses
and
effective
immune
checkpoint
blockade
(ICB)
therapy.
Here,
we
show
that
human
CD1c
+
CD5
DCs
are
reduced
in
melanoma-affected
lymph
nodes,
with
expression
on
correlating
patient
survival.
Activating
enhanced
priming
improved
survival
after
ICB
DC
numbers
increased
during
therapy,
low
interleukin-6
(IL-6)
concentrations
promoted
their
de
novo
differentiation.
Mechanistically,
was
required
to
generate
optimally
protective
hi
helper
CD8
cells;
further,
deletion
from
dampened
tumor
elimination
response
therapy
vivo.
Thus,
an
essential
component
optimal
