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*
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814
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Abstract |
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release, nor did they adversely affect the specific lysis of tumor cell
targets. These results imply that Fas-mediated activation-induced cell
death could be a limiting factor in the in vivo efficacy of adoptive
transfer of class I-restricted CD8+ T cells and provide a
means of potentially enhancing their growth in vitro as well as their
function in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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While it is clear that T cells kill tumor cells, the effect of the tumor-lymphocyte interaction on the viability of the lymphocytes themselves has not been characterized. The outcome of recurrent interaction with antigenic tumor cells can be expected to lead to either proliferation or deletion by activation-induced cell death (AICD),2 and the elucidation of this outcome is relevant to the efforts to achieve efficacious immunotherapy. In light of the recent attention given to the possibility that Fas ligand (FasL, CD95)-expressing melanoma cells actively delete Fas+ lymphocytes infiltrating the tumor bed 2, 5 , we sought to analyze both the susceptibility of tumor reactive T cell lines grown in vitro to FasL-induced cell death as well as their fate upon interaction with cognate and noncognate melanoma tumor cells in vitro. Our data support an important role for Fas-FasL interaction in the deletion of activated tumor-reactive T cells, but by a mechanism different from the one previously proposed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell lines that had been previously isolated from
tumor-infiltrating lymphocytes 6 were thawed and maintained in
Iscove’s modified Dulbecco’s medium supplemented with 10 nM
glutamine, 250 U/ml penicillin-streptomycin (Biofluids, Rockville, MD),
10% human AB serum (Gemini, Casabas, CA), and 6000 IU IL-2
(Tecin, Hoffmann-La Roche, Nutley, NJ) at 37°C in a humidified
incubator with 5% carbon dioxide. These cell lines were 
75%
CD8+, except for line 888, which was 72% CD4+
and 26% CD8+. Tumor cell lines that had previously been
established in our laboratory were maintained in similar medium, except
for the use of 10% heat-inactivated FBS (Biofluids). For CTL lines
888, 907, 1143, 1359, and 1495, autologous tumor lines were available
and used for recognition experiments. 624 is an HLA-A2+
melanoma line; 624.38 and 624.28 are HLA-A2high and
HLA-A2- clones, respectively. These lines have previously
been shown in our laboratory to be recognized by CTL 1143 and CTL 1520
in an HLA-A2-restricted manner. L1210 and the Fas-transfected clone
L1210Fas 7 were a kind gift of Dr. P. A. Henkart (National
Cancer Institute, National Institutes of Health, Bethesda, MD).
Abs and chemical reagents
Anti-Fas Abs Ab-2 and Ab-3 (a kind gift of Calbiochem,
Cambridge, MA) were used for flow cytometry analysis. Anti-Fas Abs FM-3
(a kind gift of Dr. David Lynch, Immunex, Seattle, WA) and SM1/23
(Alexis, San Diego, CA) were used as blocking Abs at the indicated
concentrations. Anti-TNF-
(Endogen, Woburn, MA) was used
where indicated. Caspase inhibitors Z-Val-Ala-Asp-CH2F
(z-VAD) and BOC-Asp-CH2F (BAF) (Enzyme Systems,
Dublin, CA) were reconstituted according to manufacturer’s
recommendation and used at a final concentration of 20 µM unless
otherwise indicated. Soluble human recombinant FasL and enhancer
protein were used as recommended by the manufacturer (Alexis).
Cytotoxicity and IFN- secretion assays
Cellular viability assays based on mitochondrial enzymatic
activity were performed with the WST-1 assay (Boehringer Mannheim,
Indianapolis, IN). Briefly, 105 cells per well were plated
in flat-bottom 96-well plates (Costar, Cambridge, MA) in triplicate
wells per condition. For each cell line, duplicate wells with varying
numbers of cells were simultaneously plated. The enzymatic assay was
performed after 24 h; a standard regression curve was plotted for
each line, and the percentage of viable cells was calculated. For
51Cr release assays, target cells were preincubated in 200
µCi 51Cr (Amersham, Arlington Heights, IL) for 90
min, washed, and plated at 5 x 103 to 5 x
104 per well in triplicate, and various numbers of
effectors were added for 16 h at 37°C, following which
supernatants were collected and counted on a -counter. The
percentage of specific lysis was calculated as (sample counts -
spontaneous counts)/(maximal counts - spontaneous counts) x
100%. Maximal release was obtained by incubating target cells with 2%
SDS, and negative values were zeroed. For IFN- release assays,
5 x 104 effectors were cocultured with
105 target cells per well in duplicate for 24 h, after
which the supernatants were analyzed by IFN- ELISA (Endogen).
IFN- levels of 100 pg/ml and at least twice as high as controls
were considered positive.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the possible induction of tumor-specific CD8+
T cell apoptosis by tumor cells, the CD8+ T cell line 1143
was coincubated at different E:T ratios with 624.38
(HLA-A2high) and 624.28 (HLA-A2-) melanoma
clones. As seen in Fig. 1
a, up
to 60% of CD8+ T cells were induced to undergo apoptosis,
but only by the tumor cells that they could recognize (as shown by
concurrent IFN- levels, Fig. 1b), indicating a
requirement for CD8+ T cell activation for apoptosis to
occur. Furthermore, apoptosis was increased as the relative proportion
of lymphocytes to tumor cells increased, suggesting that
interlymphocyte contact (as opposed to lymphocyte-tumor cell contact)
was mediating apoptosis and was in contrast to the effect of different
E:T ratios on the secreted IFN- (similar results were obtained with
T cell line 1520, data not shown). An additional four CD8+
T cell lines, assayed against autologous or non-HLA-matched tumors,
showed the same phenomena: apoptosis of the tumor-specific
CD8+ T cells depended on recognition of the tumor cells
(Fig. 2). The percentage of cells
susceptible to lysis varied between 10 and 50%, probably as a
reflection of the relative proportion of actual tumor-specific
CD8+ T cells in the line and a lower E:T ratio (1:1). These
results cannot be readily explained by expression of FasL by the tumor
cells, as this would result in indiscriminate killing. However, they
could be explained by AICD of the lymphocytes, i.e., the induction of
FasL on the lymphocytes. Thus, we turned to examining the expression of
Fas on these CD8+ T cells lines and their susceptibility to
FasL.
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To begin to delineate the role of Fas and FasL in the above
phenomena, tumor-specific CD8+ T cells were analyzed for
Fas surface expression by flow cytometry and their sensitivity to FasL
was quantified by incubation with increasing concentrations of
recombinant human soluble FasL (rhsFasL). All CD8+ T cells
lines expressed high basal levels of Fas on their surface (Fig. 3a). This expression was
relatively uniform across different lines and on average four times as
high as on the human T cell leukemia line Jurkat, which is often used
as a Fas+/Fas-sensitive target (data not shown). This high
surface expression correlated with a uniformly high susceptibility to
FasL-induced apoptotic death with an LD50 of 
10ng/ml at
12 h. (Although sFasL has recently been shown to be 1,000-fold
less active than the membrane-bound form 8 , the rhsFasL used in the
present study is a longer form than the one processed by
metalloendoproteases, and all assays were done in the presence of an
enhancer protein, which causes aggregation of rhsFasL, Fig. 3b.) This LD50 is almost as low as for L1210
cells transfected with the murine Fas (L1210-Fas). Incubation with
TNF- did not cause any apoptosis (data not shown). The apoptotic
mode of death was confirmed by Annexin/propidium iodide staining
4–6 h after treatment with rhsFasL (data not shown). The
susceptibility to the native membrane-bound form of FasL was further
confirmed by incubating CD8+ T cells with activated
allogeneic PBMC; anti-Fas mAb FM-3 effectively blocked 60% of
induced death (shown for one representative line in Fig. 4).
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Despite repeated attempts with several different Abs, we failed to
detect specific surface expression of FasL by FACS, consistent with
several recent reports of the nonspecific binding of some of these
reagents 9, 10 . As anti-CD3 stimulation with the mAb OKT-3 is an
often used model of TCR activation, which can cause Fas-dependent
apoptosis in prestimulated T cells 11, 12, 13 , we explored the effects of
TCR ligation (in the absence of a second cell that may or may not
express FasL) on the survival of the anti-tumor T cell cultures by
incubation on plate-bound anti-CD3. Activation induced the
apoptosis of 80% of the cells in these CD8+ T cell
lines, and 60–100% of this death was blocked by anti-Fas mAb
(Fig. 5a). Anti-TNF- failed
to block this death (data not shown). Similarly, anti-Fas mAb could
block the tumor-induced apoptosis, as shown for the T cell line 1143
(Fig. 5b) (similar results were obtained for T cell line
1520). To test the induction of active FasL on the cell surface of the
activated T cells, L1210 and L1210Fas cells were used as targets for
FasL-mediated cytotoxicity. T cells that had been activated on OKT-3
showed preferential lysis of Fas-transfected as compared with the
parental L1210 cells (Shown for a representative line in Fig. 6). There was minimal lysis of L1210 or
L1210Fas by unactivated T cells (not shown). None of the melanoma tumor
cells used in this study induced apoptosis of L1210/L1201Fas or
expressed FasL mRNA, as assessed by RT-PCR, whereas FasL mRNA was
induced by anti-CD3 stimulation of tumor-reactive lymphocytes 14 .
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The previous results showed that the interaction of a
tumor-specific CD8+ T cells with the cognate tumor target
can cause significant TCR-mediated AICD. This death is known to occur
later (16–24 h) than the perforin-mediated lysis of the tumor targets
and is dependent upon the interaction of FasL with the Fas receptor.
Thus, we hypothesized that this death could be blocked by specific
inhibitors of the caspase pathway, which are crucial to transducing the
Fas apoptotic signal, and indeed this was the case. The specific
peptide inhibitor z-VAD could block nearly all apoptosis mediated by
either anti-CD3 activation or interaction with cognate tumor (Fig. 7, a and b).
Similar results were obtained with the caspase inhibitor BAF, but not
with the control peptide z-FA (not shown). Although blocking this death
pathway might enhance the ability of CD8+ T cells to kill
tumor targets, it might also interfere with the susceptibility of the
tumor cells to cytolysis. Thus, we examined the effects of blocking the
Fas pathway at the surface (with blocking Abs), or downstream at the
level of the caspases, on the recognition and lysis of tumor cells
(Fig. 7, b and c). The caspase inhibitor z-VAD
did not decrease the lysis of tumor cells by the CD8+ T
cells and even increased the levels of IFN- secreted. At the same
time, blocking with the anti-Fas Ab FM-3 consistently led to a
small increase in the level of tumor lysis, while IFN- levels
remained as high. These data demonstrate that it is possible to
abrogate the detrimental effect of the T cell-tumor interaction on the
T cell without interfering with the lysis of the tumor cell.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, consistent with a
previous report where TNF- was found to function as a growth factor
in tumor-infiltrating lymphocytes 18 . The expression of FasL has been found in nonlymphoid organs, such as the testis and the anterior chamber of the eye, and presumably accounts for their "immune-privileged" status. Of specific interest has been the description of FasL expression in some tumors, notably melanoma 5 , hepatocellular carcinoma 19 , and lung cancers 20 , where its expression has been postulated to account for specific immune suppression by deleting Fas+ tumor-reactive T cells. This hypothesis would predict that the T cell lines used in our study, being highly susceptible to FasL, would be killed by melanoma cells in an MHC-unrestricted fashion. However, contrary to prediction, these T cells were lysed only when cocultured with the cognate tumor target. In theory, TCR engagement might be a prerequisite for Fas-mediated apoptosis 21 , but as these T cell lines were highly susceptible to rhsFasL in the absence of TCR engagement, the data is not consistent with FasL expression by melanoma cells. Furthermore, in concurrent studies we have not found any expression of FasL either by a functional assay or by RT-PCR with intron-spanning primers in over 20 melanoma lines (including those used in this study) chosen at random from the large bank of melanoma tumor lines established in our laboratory 14 . As the T cell lysis was inhibited by blocking the Fas pathway, we conclude that upon activation by the cognate tumor the T cells themselves express FasL and undergo suicidal or fratricidal apoptosis.
Rivoltini et al. 22 recently published their findings on the relative resistance of four melanoma tumor-reactive CTL clones to FasL, which was ostensibly expressed by some of the melanoma cell lines. However, the expression of FasL by melanoma cells was based on FACS staining with a polyclonal Ab (C-20) that since then has been reported not to bind specifically to FasL 9, 10 . As all the cytotoxic activity was demonstrated after a week of coincubation with the autologous tumor, AICD was apparently not induced in their T cell clones by the interaction with tumor. T cell clones, in comparison with the lines used in the present study, might be relatively resistant to FasL either as consequence of different in vitro conditions (cloning vs high-dose IL-2) or possibly biased selection of Fas resistant cells by the cloning procedure. Our data do agree on two key issues: 1) there is no FasL toxicity mediated by FasL expression on melanoma cells toward Fas-expressing tumor-reactive T cells, and 2) Fas/FasL is not used by the T cells to mediate lysis of tumor cells. This latter finding underlies our ability to block the T cell suicide without blocking the tumor lysis.
The molecular pathway leading to Fas-mediated apoptosis has been shown
to depend upon a cascade of Caspase proteases 23, 24 . We have
employed the previously characterized peptide inhibitors of this
pathway to block the death of the tumor-reactive CTL. The two peptide
analogues, Cbz-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-FMK) and its
truncated analogue Boc-Asp(OMe)- fluoromethyl ketone (BD-FMK or BAF),
which can block caspase 3 but not IL-1ß-converting enzyme
(caspase 1), have been shown to inhibit, at similar concentrations,
anti-CD3/Fas-induced death in both thymocytes and activated T cell
blasts 25 . Moreover, in a model of fulminant hepatic failure leading
to death of mice injected with an activating anti-Fas Ab, in vivo
administration of z-VAD could prevent liver destruction and death 26 .
These inhibitors could prevent the AICD of anti-CD3 or
tumor-stimulated T cells in our current study. As z-VAD has been shown
not only to block the death but to enable the concomitant proliferation
of Jurkat cells 27 , using z-VAD concurrently with Ag (or
anti-CD3) stimulation in vitro might enable a more efficient
expansion of Ag-specific T cells. Blocking apoptosis in vivo, while
potentially enhancing the ability of reactive T cells to kill tumor
targets, might also interfere with the susceptibility of the tumor
cells to cytolysis if their death involves Fas or caspases. Blocking
lymphocyte apoptosis with the caspase inhibitor z-VAD did not decrease
the lysis of tumor cells by CTL in our study, and even increased
slightly the levels of IFN- secreted. Thus, blocking the Fas/caspase
pathway did not impair melanoma tumor cell lysis, consistent with the
near-complete absence of surface Fas in the melanoma lines (data not
shown). Although granzyme B, the lytic enzyme of the major cytotoxicity
pathway of CTL, is a serine protease with a specificity similar to that
of caspase (Asp at P1) and has been reported to activate caspases 28, 29 , these same peptide inhibitors (z-VAD and BAF) were shown to
abrogate Fas-induced but not granzyme-induced target cell lysis 30 .
The accepted paradigm is that Fas-mediated cytotoxicity accounts for a
minor lytic pathway that functions mostly in interactions between
lymphocytes themselves. The expected exception would occur when a tumor
arises from a hematopoetic origin; CD8+ T cells have
been shown to kill Fas-expressing acute myeloid leukemia cells via the
Fas pathway 31 .
To summarize, the interaction of melanoma tumor-derived reactive CTL with the cognate tumor Ag induces Fas-dependent apoptosis of the CTL, where FasL is expressed by the tumor-reactive lymphocytes and not by the tumor cells. This sensitivity to AICD might be a limiting factor in the in vivo efficiency of such CTL when adoptively transferred to patients. The demonstration that this deletion is blockable with either anti-Fas Abs peptide inhibitors of caspase proteases without adversely interfering with recognition or lysis of tumor cells provides a possible method to modulate this susceptibility in vivo to enhance anti-tumor immune responses.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: AICD, activation-induced cell death; FasL, Fas ligand; rhsFasL, recombinant human soluble FasL.
Received for publication October 6, 1998. Accepted for publication December 14, 1998.
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References |
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ß T lymphocytes for apoptosis. Nature 353:858.[Medline]
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