Cell,
Journal Year:
2020,
Volume and Issue:
182(5), P. 1252 - 1270.e34
Published: Aug. 19, 2020
Aryl
hydrocarbon
receptor
(AHR)
activation
by
tryptophan
(Trp)
catabolites
enhances
tumor
malignancy
and
suppresses
anti-tumor
immunity.
The
context
specificity
of
AHR
target
genes
has
so
far
impeded
systematic
investigation
activity
its
upstream
enzymes
across
human
cancers.
A
pan-tissue
signature,
derived
natural
language
processing,
revealed
that
32
entities,
interleukin-4-induced-1
(IL4I1)
associates
more
frequently
with
than
IDO1
or
TDO2,
hitherto
recognized
as
the
main
Trp-catabolic
enzymes.
IL4I1
activates
through
generation
indole
metabolites
kynurenic
acid.
It
reduced
survival
in
glioma
patients,
promotes
cancer
cell
motility,
adaptive
immunity,
thereby
enhancing
progression
chronic
lymphocytic
leukemia
(CLL)
mice.
Immune
checkpoint
blockade
(ICB)
induces
IL4I1.
As
inhibitors
do
not
block
IL4I1,
may
explain
failure
clinical
studies
combining
ICB
inhibition.
Taken
together,
opens
new
avenues
for
therapy.
Frontiers in Immunology,
Journal Year:
2021,
Volume and Issue:
12
Published: May 26, 2021
The
diverse
and
dynamic
microbial
community
of
the
human
gastrointestinal
tract
plays
a
vital
role
in
health,
with
gut
microbiota
supporting
development
function
immune
barrier.
Crosstalk
between
microbiota-gut
epithelium
system
determine
individual
health
status,
any
crosstalk
disturbance
may
lead
to
chronic
intestinal
conditions,
such
as
inflammatory
bowel
diseases
(IBD)
celiac
disease.
Microbiota-derived
metabolites
are
crucial
mediators
host-microbial
interactions.
Some
beneficially
affect
host
physiology
short-chain
fatty
acids
(SCFAs)
secondary
bile
acids.
Also,
tryptophan
catabolites
responses,
through
binding
aryl
hydrocarbon
receptor
(AhR).
AhR
is
abundantly
present
at
mucosal
surfaces
when
activated
enhances
epithelial
barrier
well
regulatory
responses.
Exogenous
diet-derived
indoles
(tryptophan)
major
source
endogenous
ligand
precursors
together
SCFAs
regulate
inflammation
by
lowering
stress
immunity,
IBD,
expression
downregulated
metabolites.
Here,
we
an
overview
microbiota-epithelium-
immunity
review
how
microbial-derived
contribute
homeostasis.
discuss
therapeutic
potential
bacterial
for
IBD
disease
essential
dietary
components
fibers
systemic
Clinical Cancer Research,
Journal Year:
2018,
Volume and Issue:
25(5), P. 1462 - 1471
Published: Oct. 30, 2018
Significant
progress
has
been
made
in
cancer
immunotherapy
with
checkpoint
inhibitors
targeting
programmed
cell
death
protein
1
(PD-1)-programmed
death-ligand
signaling
pathways.
Tumors
from
patients
showing
sustained
treatment
response
predominately
demonstrate
a
T
cell-inflamed
tumor
microenvironment
prior
to,
or
early
on,
treatment.
Not
all
tumors
this
phenotype
respond,
however,
and
one
mediator
of
immunosuppression
is
the
tryptophan-kynurenine-aryl
hydrocarbon
receptor
(Trp-Kyn-AhR)
pathway.
Multiple
mechanisms
may
be
mediated
by
pathway
including
depletion
tryptophan,
direct
Kyn,
activity
Kyn-bound
AhR.
Indoleamine
2,3-dioxygenase
(IDO1),
principle
enzyme
Trp
catabolism,
target
small-molecule
clinical
development
combination
PD-1
inhibitors.
Despite
promising
results
early-phase
trials
range
types,
phase
III
study
IDO1-selective
inhibitor
epacadostat
pembrolizumab
showed
no
difference
between
epacadostat-treated
group
versus
placebo
metastatic
melanoma.
This
led
to
diminution
interest
IDO1
inhibitors;
other
approaches
inhibit
continue
considered.
Novel
Trp-Kyn-AhR
inhibitors,
such
as
Kyn-degrading
enzymes,
AhR
antagonists,
tryptophan
mimetics
are
advancing
early-stage
preclinical
development.
uncertainty
surrounding
inhibition,
ample
evidence
supports
continued
augment
immune-checkpoint
therapies.
