Download How Do Lymphocytes Kill Tumor Cells?1

Vol.
2, 785-789,
May
1996
Clinical
Cancer
Research
785
Minireview
How
Do Lymphocytes
Timothy
A. Graubert
Departments
of Medicine
Transplantation
Medical
and
School,
and
Genetics,
Cell
Biology,
St.
Louis,
Division
of
Bone
Washington
Missouri
Tumor
Cells?1
tumor
J. Ley2
Timothy
and
Stem
Kill
63110
and surgery
Still, nearly
disease
have
50%
soluble
of primary
diverse
had
strong
system,
radiotherapy,
appeal
cancer
resistance
able
responses
intuitive
effective
or acquired
immune
and cell-mediated
more
of chemotherapy,
had a significant
impact
on cancer
mortality.
of the adult
victims
of cancer
die of their
as a result
enormously
has
modalities
to as many
risk
erations
that
stored
(e.g.
of developing
regress
(2).
The
occasionally
system
(e.g.,
tumor
of the
immune
surveillance.
cific antigens
are the basis
The
system
generation
not
subjects
be
have
discussed
been
is resurveil-
can
(4,
strategies
the scope
recently
5).
Coverage
using
of this
tumor
activity
lymphocytes
Cell-mediated
they
LAK
phenotype
evidence
role
host
response
and
macrophages)
phagocytes
in the
(neutrophils
suggesting
but will not be discussed
lymphocyte
compartments
that
lymphocytes
to tumors.
Nonspecific
may
further
here.
also
in cell-mediated
I
This
10/10/95;
work
DK38682
2
is
in-
against
and
To whom
Internal
the
The
for
Medicine,
receptor;
crmA,
NIH
should
cytokine
be
University
CA497
12,
DK49786,
and
agreement.
addressed,
School
at Department
of
used
are:
TNF,
Fas
response
ligand;
modifier
tumor
necrosis
killer;
gzm,
ICE,
interleukinA.
of
Medicine,
660
Box 8007, St. Louis, MO 63110. Phone:
362-9333;
E-mail: [email protected].
lymphokine-activated
FasL,
Grants
University-Monsanto
reprints
Washington
abbreviations
LAK,
by
Washington
requests
South Euclid Avenue,
362-9337;
Fax: (314)
killer:
12/6/95.
accepted
supported
factor;
granzyme;
1 converting
NK,
(314)
natural
FasR,
enzyme;
also
able
lymphoma)
participate
cell
LAK
but
in tumor
targets
tumor
cells
with
without
lines
but
are derived
acquire
may
assume
with
IL-2
biochemical
it from
and
necrotic
apoptosis
level
several
sensi-
chronic
cells
and
potent
anti-
exposure
to IL-2. Tumor-infiltrating
for specificity
to the tumor
from
incubated
unique
(of
Circumstantial
to lyse
cells.
to NK
explanted
when
distinguish
has
through
years,
Effector
cell
been
the
nonspecific
in vitro.
by inducThis is
morphological
death
(12).
features
The
characterized
process
of
extensively
genetic
experiments
the results
of which
Fas
Pathways
Cytotoxicity
The Granule
anisms
ently
way.
at
performed
durare summarized
susceptible
target
alignment
of their
for Cell-mediated
Pathway.
cytotoxicity
in lymphocytes.
In this pathway,
appear
Two molecular
to have
evolved
mech-
independ-
The first is the granule
exocytosis
the recognition
and tight binding
cell
by
a CTL
secretory
or NK
cell
apparatus,
causes
promoting
material
target
sufficient
cell.
One
[cytolysinlpore-forming
to initiate
granule
vectorial
a protein
with
signifi-
homology
to the terminal
components
of complement
Ca2-dependemt
polymerization
of perform
on the
cell
membrane
forms
deliver
the lethal
neutral
serine
experimental
brane
damage
target
cells,
a channel
gain
hit (Ref.
proteases
causing
but
it was
tation, the sine qua
gzm B alone
was
together
resulted
similar
experiment,
cell line became
leakage
not
1). The
are critical
test of this model,
which
to the target
Fig.
15;
that
through
access
purified
sufficient
for this
perform
to trigger
ofapoptosis
(16-18).
ineffective.
Perform
and
non
other
(14).
target
granule
cell cytoplasm
gzms
of cytoplasmic
pro-
is perform
cant
The
probably
of
membrane
secretory
an apoptotic
constituent
(PFP)1,
protein
pathof a
delivery
cytoplasmic
granules
to the target cell
close
intercellular
contact
(13).
These
contain
in the
Account
Exocytosis
of cellular
constituents
Received
are
prototypical
common
CTL-induced
gram
by all
cytotoxicity
may
(9).
T cells
Lymphocytes
kill targets
(including
tumor cells)
ing them to undergo
programmed
cell death (apoptosis).
granules
be
Participation
The
were
electron-dense
at areas
of
to Tumors
is abundant
a central
cella role for
killing.
Response
There
cells
only upon
are enriched
which
Two
will
of immunotherapy
cell
in tumor
cytolytic
cells
peptides.
that CD4
below.
gene-transfer
techniques,
is
review
(6, 7). Here, we will
this
be
NK
NK
T-cell
a precursor
the molecular
ing the past
lymphoactivity.
and
mechanisms
of contact-dependent,
and the evidence
that suggests
pathway
in
aberrantly
has reached
elsewhere
also
that
11).
(murine
from
a process
to tumor-spe-
focus on the molecular
mediated
cytotoxicity
volved
subclass)
Thl
tumor-specific
clear
cells
prolif-
such as TNF3, IFN-y,
have potent antitumor
reviewed
further
trials,
including
likewise
beyond
play
the
to identify
it is now
YAC-l
of tumors
or to host antigens
that are expressed
of the tumor
vaccine
effort,
which
used
(human
to be involved
of antibodies
clinical
trials. Soluble
mediators
toxin, and other cytokines
clearly
These
appear
been
initially,
that
arms
have
disputed
tive to NK-mediated
lysis in vitro
are K562
myelogenous
leukemia-derived
erythroleukemia)
(3).
All
and
Although
ligands,
to find
of immune
transferred
hosts (8). This property
is specific
and long-lived.
CD8
and CD4
T cell clones
can be propagated
sensitization.
medications,
or
transplants)
are at
as evidence
can provide
adoptively
previous
if immunocompetence
taken
when
specific
is active
patients
in-
regression
tumors
of experimental
animals
(10,
or monoclonal
spontaneous
is also
syngeneic
a variety
immunized
suggests
hoping
the immune
hosts
oligoclonal
occasional
melanoma)
,
lance
as lO
for investigators
fected
with HIV, receiving
immunosuppressive
recovering
from solid organ or bone marrow
increased
against
using
from
rejection
The
).
therapies.
There
is good evidence
that
against
tumors.
Immunocompromised
T cells
evidence
(1
to generate
implicated
CD8
into naive
Furthermore,
in vitro
combined
has been
immunity
University
Introduction
The
cells
approaches.
Marrow
to
are a family
process.
In one
induced
mem-
contents
DNA
of
from
fragmen-
Purified
gzm A or
gzm A or gzm B
in the apoptotic
death of the target
the monlytic
RBL (rat basophilic
weakly
cytotoxic
when
transfected
cell. In a
leukemia)
with the
Downloaded from clincancerres.aacrjournals.org on April 28, 2017. © 1996 American Association for Cancer
Research.
786
Cell-mediated
Tumor
Immunity
Fig.
1
Perforinlgzm
pathways
of
totoxicity.
At
tercellular
sites
tumor
branes,
probably
enter
the
cell
where
substrates
(possi-
the
(19).
Transfectants
expressing
in target cells. In triple transfectants,
(in the presence
of perform)
to
surface
of
receptor
in the context
signals
the genes encoding
proteins
(20-22).
NK
contain
up-regulation
of
the
generated
preformed
toxic
granules
of development)
and conseto trigger
the formation
of
use
with
of gene-targeting
null
technology,
mutations
at several
mice
critical
CD8
a severe
target
compromised
YAC-l
tumor
gzm
cells
defects
virus)
(24,
(24).
The transduction
signal
may
CD8
by
of the cowpox
a
vi-
in susceptible
or prolonged
disease
model
T cells
on
perforinlgzm
is inhibitable
apoptosis
ratios
of this
converge
the
and
FasL,
lympho-
death
induce
B-deficient
true
for
NK
against
mice
clearance
as impaired
incubation
used in our
demonstrate
allograft
the
CTLs
and
LAK
cells
were
CTLs
exhibit
a
ability
to induce
apoptosis
rapidly
in
(26), but cytotoxicity
recovers
partially
with
target
CTLs;
24).
In contrast,
Ref.
cells
(as
still
that CD8
cells
is
gzm
impaired
a reduc-
in the terminal
are
some
devoid
CTLs
a second
loaded
and are
Chddiak-
Ch#{233}diak-Higashi
These
killing
observations
pathway
but that
do not.
CTLs with an ineffective
cytosis
sidual
pathway
cytotoxicity
antigen,
a cell
surface
receptor
family.
The
purification
T-cell
of FasL, a membrane-bound
activation
(32). The
of
from perform-deficient
only against
target cells
FasR
receptor
and
related
structurally
of the FasR
FasL
triggers
through
unknown
it is argued
that
role
granule
to the TNF
led to the cloning
protein
that
Ca2-independent
target
cell
deleting
activated
T cells),
apoptosis
tail of the FasR
the death
signal
mechanisms
(Refs.
33-35;
Fig.
the Fas pathway
serves
primarily
(by
exo-
mice) exhibit
rethat express
the Fas
(i.e.,
through
a “death
domain”
on the cytoplasmic
via a series
of docking
proteins
that transmit
regulatory
and
granules
Although
of cytotoxicity.
have
of
from these
pathway.
synthesized
cytotoxicity,
as
phase
cells,
and neutrophils
in the granule
exocytosis
granules
exhibit
cell-mediated
to infection,
aberrantly
with secondary
nonfunctional
(30, 31).
are virtually
and characterization
induced
during
choriorejection
of effectors
azurophil
they fuse
completely
interaction
CD8
incubation
perform-deficient
Although
have
susceptibility
disorder
The Fas Pathway.
the NK-sensitive
also exhibit
pro-
(lymphocytic
cardiac
patients
in increased
as a lymphoproliferative
properly,
rendered
NK
standard
against
cells
These
resulting
suggest
25).
severe
defect
in their
susceptible
target cells
prolonged
Perform-deficient
in viral
as well
B-deficient
with
lymphocytes
using
defect in cytotoxicity
similarly
when directed
cells. Perform-deficient
in vivo
responses
gzm
syndrome.
immunity,
NK cells
en-
analysis
of perform-deficient
lytic assays demonstrated
meningitis
cannot
tumor
the
in cytotoxic
activity,
but CD4
T cells do not (28).
A human
model for the complete
disruption
of the granule
exocytosis
pathway
is provided
by patients
with Ch#{233}diak-Hi-
Higashi
have
loci
pathway
proteins.
These loss-of-functhe model presented
above.
in vitro
found
cells
the illness
(29). CTLs,
NK
patients
have a severe
defect
(generated
coding granule
exocytosis
tion mutants
have validated
allogeneic
laboratory,
well
gzm A, gzm B, and other granule
becomes
fully armed
within
3-5
(23).
Through
been
NK
cells,
despite
high E:T
In an acute graft-versus-host
gashi
the appropriate
and
in transcriptional
perform,
The Cli
cells
of these molecules.
of antigen
by its
of self-MHC
results
presumably
at a precursor
stage
quently
do not require
sensitization
granules
yield
A and B synergized
even higher
levels
of
cells differ in their expression
of a T cell upon recognition
costimulatory
days.
gzm
target
(27).
most
by
cytes.
in
in-
present
cytotoxic
substrates
B-deficient
perform
of apoptosis
be
FasR,
is engaged
pathway
Alter-
may
tion
cytotoxicity.
Effector
The activation
surface
both
all of the hallmarks
death.
the
on
in
fragmentation
cell
gene product
rus, crmA.
B generated
events
culminate
DNA
when
present
A or gzm
proteolytic
apoptosis
targets,
for perform
of the
members
apoptotic
duced
and gzm
gzms
cytoplasm,
defined)
natively,
cDNA
mem-
Subsequent
yet
tumor
on
perme-
cell
by
cleavage.
and
that
allowing
family)
(not
release
target
activate
ICE
in-
containing
a protein
abilizes
bly including
Tumor
Target
tight
cyto-
granules
perform,
Perform
cy-
of
lymphocytes
secretory
they
Fas
conjugation,
toxic
to
and
cell-mediated
1). Although
an immunoFas-dependent
Downloaded from clincancerres.aacrjournals.org on April 28, 2017. © 1996 American Association for Cancer
Research.
is
Clinical
cytotoxicity
readily
against
nonlymphoid
occurring
mutations
for the Fas pathway
with
the gid mutation
region
of FasL
signal
(39).
animals
quence
failure
FasL-deficient
effectors
demonstrate
(43).
FasL-deficient
in cytotoxicity.4
but this is only
B-deficient
background.
patients
T-cell
deletion
these
patients.
and
and
patients
(46).
There is strong
pathways
are
pathways
for
pear to utilize
evidence
all
seems
pathway
as noted
For
not yet been
Caenorhabditis
critical
(49).
elegans
cleaves
protein
gzrn
coagulation
ognition
B.
This
ase
system.
that crmA,
cross-class
inhibitor,
(gzm
B) and
Ref.
50).
The
ated
by Fas,
evolved
to
in these
may
represent
a novel
road
to
that
these
cell-
no cytoxicity
depend
is
on both
but CD4
CTLs
NK cytotoxicity,
the
granule
apin
exocytosis
TNF,
An
a human
homologue
after
the granule
a proteolytic
inhibiting
acid
residues;
coincidence
of
substrate
exocytosis
cascade
pathway
reminiscent
came
of the
protease
that
B (5l)
system,
with
cascade,
both
family
crmA
and
the rec-
(e.g.,
apoptosis
further
independent
may
of
virus,
a serine
members
blocks
reinforces
two
with
cowpox
specifically
or gzrn
this
was
of CED-3,
aspartic
clue
product
on a final common
pathway
that a system
of protease
to regulate
clue
for development
in the nematode
ICE is the second
protease
iden-
An additional
cysteine
important
is a
prote-
ICE;
medi-
the analogy
initiation
arms
(Fig. 1). It is tempting
inhibitors
may have
that
exploitation
of this
Fas and Granule
Exocytosis
Tumor
Cell Killing in Vivo
the
killing.
were
The
described
have
been
Perform-deficient
tumor
cells injected
(24).
the
tissue
munity.
However,
defects
above.
To date,
B propathways
in allogeneic
only
tumor
a few
in vivo
allogeneic
wild-type
P815
litter-
performed.
tumor
possibility
logeneic
perforin/gzm
of these
in vitro
mice were able
i.p. as effectively
Nonsyngeneic
formal
rather
in
models
that
rejection
an
to lyse
as their
such
tumor
than
as this,
clearance
tumor
additional
however,
represents
al-
antigen-specific
experiment,
im-
the
footpad
swelling
response
to the intradermal
injection
of syngeneic
MC57G
fibrosarcoma
tumor
cells was significantly
greater
in
perform-deficient
mice,
indicating
compromise
of CD8-dependent
tumor
rejection
In an in vivo
the gzm
in these
tumor
ing the oncogenic
B-deficient
no significant
perform-deficient
cells
on
unusual
a gene
demonstration
to the coagulation
converging
to speculate
noted
targets,
substrates
specificity
suggested
that
initiate
apoptosis
through
the
susceptibility
when
identified.
of ICE,
gene
was
by
with
intermediates
that link the signals
delivor Fas to nuclear
events
resulting
in
by the cloning
first
is shared
above.
a death-inducing
that
been
clonal
to suggest
and LAK
entirely
also
present
been
cytotoxicity,
the Fas pathway.
to depend
have
provided
example,
CTLs
have
contact-dependent,
FasR-deficient
CD8
The intracellular
by perforin/gzms
apoptosis
nearly
corn-
peripheral
cell
killing
raise
on a gzrn
mice
yet
for
cell-mediated
primarily
contrast,
not
experimental
to kill
(47, 48).
of
increased
have
account
used
detectable
superimposed
cell
mates
reduction
individuals
autoimmunity;
cytotoxicity.
CTLs
tified
affected
malignancy
in the
in the CD8
or FasL-deficient
Clinically,
lymphadenopathy
mediated
products
The null mutations
of FasR/FasL
and
critical
reagents
to test the importance
experiments
disease
a profound
failure
T
using
primarily
of FasR
The
in FasR-
assays
graft-versus-host
mutations
45).
cytotoxicity
when
Mediate
for tumor
as a conseof activated
reduced
apparent
(44,
seen
T cells
That
Pathways
vide
(40).
deletion
have
is also
with
recently
infections
CTLs
Cytoxicity
Human
gene
Evidence
causing
phenotype
defects
In an acute
CD4
partment,
identified
CD8
in vitro
in a
of the apoptotic
a mutation
in a similar
CD4
(41, 42).
compartment
model,
viral
Mice
substitution
have
of Fas-dependent
in the periphery
recently.
nucleotide
mice
results
accumulate
of the
CD4
by
787
loss of function
identified
for transmission
lpr
that
been
a single
is critical
of FasR
These
cells
have
that
that provide
have
Conversely,
truncation
the
system
be demonstrated
Research
neoplasia.
Naturally
ered
can
(36-38).
models
two
targets
Cancer
lckrHOX11
background.
difference
B-deficient
suggesting
this model.
simplifies
compared
with
B is not critical
FasR-
mocyte
the
and
interpretation
or FasL-deficient
development
and
of
report
such
mice.
peripheral
does
mice
(52).
Class
ated
and
Within
els has
yield
I- and
are
reduction
phenotype
class
not yet been
important
soluble
in vivo.
Il-deficient
normal
One
compartments
in
These
recent
role
administration
with FasL
model,
from
been
animals
the
cell-mediated
will
to
gener-
a profound
respectively.
or clearance
the role
of
cDNA
is sufficient
have
about
for
encapsulated
of syngeneic
experimental
T cells,
surveillance
analyzed.
information
caused
and autoiminterpreta-
effector
FasL
apart
in
in thy-
making
animals
developmentally
studied
difficult.
of this
that
cells
for a
clearance
a death
the constraints
in CD8
and CD4
in syngeneic
tumor
phocyte
been
apoptotic
death
of
in the peritoneal
cavities
this finding
demonstrates
cause
apoptosis
of tumor
This
Data
to interpret
against
tumors
in vivo;
i.p.
from
a cell line transfected
dose-dependent
cells implanted
is quan-
experiments.
T cell
indirectly
in
animals.
Abnormalities
potentially
demonstrate
this pathway
supernatants
caused
YAC-l
experiments
controls,6
surveillance
B-deficient
of these
a gzm
there was
of tumors
in
compartments
gzm
by these mutations
leads to lymphoproliferation
mune
disease
in these
animals,
however,
tion
into
wild-type
from the following
experiments
is not as easy
number
of reasons,
as outlined
below.
Killing
of syngeneic
tumors
has not
either
overexpress-
bred
for immune
of the lymphocyte
in perform
greatly
mice
were
After 1 year of observation,
in the incidence
or latency
The composition
normal
(24).
model,
transgene
cohort,
that gzm
titatively
animals
surveillance
Their
mod-
potentially
of individual
lym-
response
tumors.
“T. Graubert,
J. Russell, and 1. J. Ley, unpublished
L. Shi and A. Greenberg,
personal communication.
observations.
6
T. Graubert,
S. Korsmeyer,
and T. J. Ley, unpublished
observations.
Downloaded from clincancerres.aacrjournals.org on April 28, 2017. © 1996 American Association for Cancer
Research.
to
788
Cell-mediated
Tumor
Immunity
I 1. Karre, K., Klein, 0. 0., Kiessling,
R., Klein, G., and Roder, J. C.
Low natural in vivo resistance
to syngeneic
leukaemias
in natural
killer-deficient
mice. Nature (Lond.), 284: 624-626,
1980.
Conclusions
The
exocytosis
experiments
described
above
and Fas pathways
may fully
suggest
account
mediated
by CTLs
tumor
in vitro
onstrate
rally
and NK cells
disruption
occurring
munity.
mutations
Although
differentially
CTLs,
in
once
CTLs),
tion
signal
(Fas
both
is delivered
possibly
involving
for
pathways
a proteolytic
of the signal
Spontaneous
tumors
not been
observed
animals
with
rate
in any
effector
pathways
reflects
have
of these
the significant
not be surprising
redundancy
if a tumor
are disabled,
either
by
transgenic
overexpression
among
phenotype
the importance
of
observation
likely
emerges
pathways
breeding
mutant
lines together
or by
of inhibitors
like crmA that act late in
new
insights
into
means
host
defenses
should
therapeutic
follow.
strategies
by which
tumor
Hopefully,
that
will
this
capitalize
cells
circumvent
lead
on this
in turn
D. M., Aebischer,
to
17.
Hayes,
M. P., Berrebi,
18. Shi, L., Kam,
A. H. Purification
of the manuscript.
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How do lymphocytes kill tumor cells?
T A Graubert and T J Ley
Clin Cancer Res 1996;2:785-789.
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