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*
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy;
Department of Oncology and Neuroscience, University of Chieti, Chieti, Italy;
Department of Experimental Medicine and Biochemistry, University of Tor Vergata, Rome, Italy; and
§
Human Genome Sciences, Inc., Rockville, MD 20850
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has recently been reported that activated monocytes mediate their tumoricidal activity via the membrane expression of TRAIL (9). Moreover, systemic administration of TRAIL trimers induces apoptosis of many cancer lines without the deleterious side-effects of CD95 ligand (CD95L) or TNF (10). Since TRAIL appears to rapidly exert potent antitumor activity by selectively and directly activating tumor cell apoptosis (8, 9, 10, 11), this finding opens intriguing new perspectives in the treatment of cancer (4, 11). However, the TNF family members are involved in a basic regulation of immune responses by biasing the action of T cells that encounter Ag toward either activation (12) or apoptotic (13, 14, 15) pathways. This paper reports that mouse mammary adenocarcinoma cells (TSA) (16) engineered to express TRAIL on their membrane (TSA-TRAIL) are better suited to overcome tumor-specific immunity and grow across minor and major histocompatibility barriers than wild-type parental cells (TSA-pc). The eventual rejection of TSA-TRAIL cells by allogeneic mice does not result in a significant boosting of a specific immune memory, since TSA-TRAIL cells appear to induce apoptosis of activated T lymphocytes.
These findings do not conflict with the use of soluble TRAIL in the treatment of cancer. They do, however, show that its expression on the cell membrane is an effective way to evade an immune reaction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The TRAIL gene used in these studies was cloned at Human Genome Sciences Inc. (Rockville, MD) through an expressed sequence tag (EST) database search by limited homology to the mouse Fas ligand (17). The complete reading frame for the TRAIL was placed under the control of a CMV promoter in the pCDNA3 plasmid (Invitrogen, Carlsbad, CA). This expression vector contains the neomycin resistance gene and was used for stable transfections of TSA-pc cells. Cells were plated at a density of 6 x 105 cells/100-mm tissue culture plate, incubated overnight at 37°C in DMEM with 4.5 g/L glucose (DMEM medium) and 10% FBS (BioWhittaker, Walkersville, MD), and then suspended in OptiMEM without FBS cells and transfected with 10 µg pCDNA3-TRAIL DNA using LipofectAMINE reagent (Life Technologies, Rockville, MD). Forty-eight hours after transfection, the cells were split at a ratio of 1:10 and plated in DMEM medium with 1 mg/ml of G418 (Schering-Plough, Milan, Italy). Clones were isolated and subcloned by limiting dilution 15–20 days later. TSA-neo is a control clone transfected with the neomycin resistance gene only.
Anti-TRAIL Abs
TRAIL cDNA was expressed in Escherichia coli. Rabbits were immunized with 0.5 mg of renatured TRAIL protein obtained from bacterial pellets and purified by chromatography on a nickel-NTA chelate column. The anti-TRAIL IgG were affinity purified on protein A-Sepharose (Amersham, Pharmacia Biotech, Uppsala, Sweden).
In vitro cultures
In vitro cultures were performed with sterile disposable glassware from Nunc, Roskilde, Denmark, at 37°C in a humidified atmosphere with 5% CO2, using RPMI 1640 medium (BioWhittaker, Milan, Italy) supplemented with 10% FBS, 50 µg/ml gentamicin, 2.5 x 10-5 M ß2-ME (Sigma, Milan, Italy), except when otherwise specified.
Tumor
TSA-pc are a cell line from a moderately differentiated mammary adenocarcinoma that arose spontaneously in a BALB/c mouse (16). TSA-pc express MHC class I, but not class II, molecules, secrete G- and GM-CSF and TGF-ß1, and do not stimulate a syngeneic antitumor response in vivo or in vitro (16, 18, 19). Similar features are displayed by TSA-TRAIL (data not shown). F1-F is an in vitro-transformed newborn BALB/c mouse-derived skin fibroblast line that does not immunologically cross-react with TSA-pc (20). Inocula of 5 x 104 and 104 cells are about the minimal 100% TSA-pc and F1-F tumor-inducing doses in BALB/c mice. In a few experiments, mice were preimmunized against TSA-pc by challenging them in the right flank with 105 living TSA cells engineered to release 40 U of IL-4/105 cells/ml in 48 h incubation (20). Those without tumor 1 mo after challenge were used as TSA-pc-immune mice. P815 mastocytoma (H-2d) and EL-4 (H-2b) lymphoma were cultured as nonadherent cell cultures.
Mice
Seven-week-old female nu/nu (CD1), BALB/c (H-2d), DBA/2 (H-2d), C57BL/6 (B6) (H-2b), and C3H (H-2k) (Charles River Laboratories, Calco, Italy) were treated in accordance with the European Union guidelines. When required, starting 2 days before tumor challenge and 4 h after, and then weekly, a few mice received i.p. injections of 100 µg anti-CD8 (TIB-105 hybridoma, American Type Culture Collection, Manassas, VA) or normal rat Ig purified through an anionic exchange column (DE 52, Whatman, Maidstone, England). Cytofluorimetric analysis of the residual blood and spleen cells from mice receiving these Abs showed that target leukocytes were selectively decreased to 1/5000 of peripheral blood leukocytes during treatment.
In vivo evaluation of tumor growth
Mice were challenged s.c. in the left flank with 0.2 ml of a single cell suspension containing the indicated number of tumor cells. The cages were coded, and neoplastic masses were measured with calipers in the two perpendicular diameters twice weekly for 120 days in a blind fashion. Tumor-free mice at the end of this period were classed as survivors. Latency and survival times were considered as the periods (in days) between challenge and the growth of neoplastic masses of 3 and 10 mm mean diameter, respectively. Only mice that eventually developed tumor were considered. Mice were killed for humane reasons when the tumor exceeded 10 mm mean diameter.
Morphological analysis
For histological evaluation, tissue samples from groups of five
mice were fixed in 10% neutral buffered formalin, embedded in
paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin
or Giemsa. For immunohistochemistry, acetone-fixed cryostat sections
were incubated for 30 min with the following Abs: anti-MAC-1,
anti-MAC-3, anti-I-A/I-E, anti-IL-6, anti-VCAM-1
(PharMingen, San Diego, CA); anti-granulocytes (RB6-8C5, kindly
provided by Dr. Coffman, DNAX, Palo Alto, CA); anti-CD4,
anti-CD8 (Sera Laboratories, Crawley Down, Sussex, U.K.);
anti-IL-1ß (Genzyme, Cambridge, MA); anti-TNF-
(Immuno
Kontact, Frankfurt, Germany); anti-IFN-
(kindly
provided by Dr. Landolfo, Torino University, Italy);
anti-inducible NO synthetase (iNOS) (Transduction Laboratories,
Lexington, Ky); anti-CD31, anti-CD62 (kindly provided
by Dr. Vecchi, Negri Nord, Italy); anti-ICAM-1 (CD54, Santa Cruz
Biotecnology, Santa Cruz, CA). After washing, the sections were
overlaid with biotinylated goat anti-rat, anti-hamster, and
anti-rabbit and horse anti-goat Ig (Vector Laboratories,
Burlingame, CA) for 30 min. Unbound Ig was removed by washing, and the
slides were incubated with avidin-biotin complex/alkaline phosphatase
(Dako, Glostrup, Denmark). Quantitative studies of the
immunohistochemically stained sections were performed by three
pathologists in a blind fashion on three or more samples from distinct
mice by evaluating ten randomly chosen fields in each sample. For cell
counts, individual cells were counted under a microscope (x40
objective and x10 ocular lens; 0.18 mm2 per
field). The expression of cytokines and adhesion molecules was defined
as absent (-) or as scarcely (+), moderately (++), or frequently (+++)
present on cryostat sections tested with the corresponding Ab. For
electron microscopy, specimens were fixed in cacodylate buffered 2.5%
glutaraldehyde, postfixed in osmium tetroxide, and then embedded in
Epon 812. Ultrathin sections were stained with uranyl acetate-lead
citrate.
Flow cytometry
TSA-TRAIL and TSA-pc from tumors grown in vivo were incubated with a 1:10 dilution in HBSS-azide-BSA of normal mouse Ig or mouse mAb to H-2Kd (clone 31-3-4S) and H-2Dd (clone 34-5-8S) (Cedarlane, Hornby, Ontario, Canada) or to H-2Ld (clone 28-14-8S) (Litton Bionetics, Charleston, SC) followed by incubation with FITC-F(ab')2 goat anti-mouse Ig (Technogenetics, Milan, Italy). Cultured TSA-TRAIL and TSA-pc were incubated with 1:10 dilution of normal rabbit IgG or anti-TRAIL rabbit IgG followed by incubation with PE-F(ab')2 goat anti-rabbit Ig (Biosource, Camarillo, CA). Dead cells were gated on the basis of forward and sideways scatter. All labeling steps were followed by incubation for 30 min at 4°C, and separated by two washes with HBSS-azide-BSA. In each experiment, 104 viable cells were analyzed with a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).
Mixed lymphocyte reactions
MLR were performed either in triplicate in the wells of 96-well,
flat-bottom plates or in 75-cm2 culture flasks
with culture medium supplemented with 4% FBS only as previously
described in detail (20). Responder nylon wool effluent
spleen cells (>90% Thy 1.2+) or mesenteric
lymph node cells (4 x 105/well or 25
x 106/flask) were cultured for 5 days either
alone or with the same number of allogeneic spleen cells pretreated
with mitomycin C. In a few cases, progressive numbers of mitomycin
C-pretreated TSA-TRAlL or TSA-pc were added at the beginning of the
cultures as third party cells. Each well was pulsed with 1 µCi of
[3H]TdR for 8 h before harvesting.
[3H]TdR uptake was assayed in a liquid
scintillation spectrophotometer, and the data were expressed as
cpm.
Cellular cytotoxicity
Cytotoxicity was evaluated in a 4-h sodium [51Cr]chromate or 48-h [3H]TdR release assay by mixing in triplicate various concentrations of effector lymphocytes with 5 x 103 labeled target cells at 50:1, 25:1, 12:1, and 6:1 E:T ratios as previously described in detail (20). The results were expressed as lytic units20/107 cells (LU20), calculated according to the equation of Pross et al. (20).
Apoptosis TUNEL analysis
Apoptosis was evaluated by fluorochrome labeling of DNA strand breaks by means of the TdT assay, using the Apo-Direct kit from PharMingen. This procedure allows the detection of apoptotic cells simultaneously with their DNA content (21). Early apoptotic cells can be detected by uptake of FITC-dUTP only, while later apoptotic cells can be detected as a hypodiploid population (21). B6 lymph node and spleen cells (106) stimulated by BALB/c spleen cells for 3 days in MLR were cocultured overnight on monolayers of 2 x 105 TSA-TRAIL or TSA-pc, in medium or in the presence of 50 µg/ml of anti-TRAIL IgG, 50 µM of Z-Val-Ala-Asp (O-methyl)-fluoromethyl ketone (ZVAD-fmk), or 100 µM Ac-Y-Val-Ala-Asp (O-methyl)-cloromethyl ketone (YVAD-cmk) (Calbiochem, San Diego, CA), two specific inhibitors of caspase-1, or 1% DMSO as control. ZVAD-fmk and Ac-YVAD-cmk were dissolved in DMSO to yield a 10-mM stock solution. Recovered lymphocytes (106) were washed twice with PBS supplemented with 0.2% BSA and 0.05% sodium azide and suspended in 0.5 ml of PBS. Five milliliters of 1% paraformaldehyde in PBS was added, and the suspension was placed on ice for 15 min. Cells were then washed twice, 5 ml of ice-cold 70% ethanol was added, and the samples were stored at -20°C until use. Each sample was incubated for 60 min at 37°C with TdT enzyme and FITC-dUTP in a reaction buffer. The cells were washed and resuspended in 1 ml of propidium iodide and RNase solution, and then incubated for 30 min at room temperature. Samples were analyzed by flow cytometry within 3 h of staining.
Statistical analysis
The significance of differences (p <
0.01) in tumor takes was evaluated by Pearson’s
2 test, whereas those in survival and latency
time and in vitro data were evaluated by a two-sample Student
t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TSA-pc are scarcely immunogenic in syngeneic BALB/c
(H-2d) mice, where they grow aggressively to form
a poorly differentiated mammary adenocarcinoma (16, 18).
They spontaneously secrete TGF-ß, vascular endothelial growth factor,
and GM-CSF (18), like most human and mouse tumors
(19), and are easy to engineer genetically. The growth
pattern and the modulation of immunogenicity of TSA cells transfected
with many distinct membrane molecules and cytokines have been studied
in detail in various laboratories (see a database in Ref.
18). This background information, along with the
availability of early in vitro passages of TSA cells stored in liquid
nitrogen, has allowed straightforward comparisons (18, 22). The selected clone (B021129) of TSA-pc transduced with the
cDNA-encoding human TRAIL (TSA-TRAIL) displays the mRNA specific for
TRAIL in Northern analysis (not shown) and expresses surface TRAIL
protein (Fig. 1
A), while still
spontaneously secreting similar amounts of GM-CSF, TGF-ß, and
vascular endothelial growth factor as the TSA-pc (not shown). TSA-pc,
TSA-neo cells engineered with control construct only, and TSA-TRAIL
cells showed similar in vitro doubling times without major apoptotic
deaths during both the exponential growth phase and at cell confluence,
as detected by the TUNEL technique. These data rule out the possibility
that fratricidal killing due to TRAIL membrane expression significantly
affects TSA-TRAIL growth in vitro. Data obtained with TSA-pc and
TSA-neo never differed significantly, and only the former will now be
shown.
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). When BALB/c mice were depleted of
CD8+ lymphocytes, TSA-pc grew faster and this
difference disappeared. Morphological observations 3 days after
challenge showed that TSA-TRAIL and TSA-pc formed a solid tumor
invading the fibroadipose tissue. At the 7th day, TSA-TRAIL tumor
masses were larger and displayed an evenly distributed vascularization
without evidence of a major apoptotic death, nor the necrotic areas
irregularly present in TSA-pc tumor. The reactive infiltrate of both
tumors was scanty, and the macrophage and CD4+
lymphocyte content of TSA-TRAIL tumor was significantly higher than
that seen in the TSA-pc tumors (Table II). Immunohistochemistry revealed a
slight expression of adhesion molecules by the well-developed
vascularization of TSA-TRAIL tumor. Proinflammatory cytokines were
poorly expressed in both tumors, though TNF- was moderately
expressed in TSA-TRAIL tumor (Table II).
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Previous studies have suggested that TSA-pc are apparently
nonimmunogenic in BALB/c mice. However, a challenge with TSA cells
engineered to release cytokines is often rejected by most BALB/c mice
and elicits the strongest TSA-specific immune response. The memory
elicited by TSA-pc engineered to release IL-4 is among the strongest
and is mostly based on TSA-specific CD8+ T
lymphocytes (22). Following TSA-IL-4 immunization, all
mice rejected TSA-pc, whereas none of them rejected TSA-TRAIL cells
(Table III).
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One million TSA-TRAIL or TSA-pc always grew in DBA/2 mice, which
have the same MHC as BALB/c mice, but differ at multiple minor
histocompatibility Ags. However, TSA-TRAIL cells grew faster (Fig. 1
B). A challenge of 105 TSA-TRAIL
cells gave rise to progressively growing tumors in all DBA/2 mice,
whereas the same dose of TSA-pc was rejected by most of them, and the
progressively growing tumors grew more slowly (Fig. 1C).
Morphological evaluations 3 and 7 days after challenge showed that
TSA-TRAIL tumor growth areas were almost similar to their counterparts
in BALB/c mice, though some intratumoral necrotic areas were present.
The TSA-pc tumor, on the other hand, was almost completely
disaggregated by a massive reactive infiltrate in which macrophages and
lymphocytes (CD8+ > CD4+)
predominated (Fig. 2, a and
c). The endothelial cells surviving from vascular damage
strongly stained for adhesion molecules (not shown), while the whole
TSA-pc growth area intensely stained for the proinflammatory cytokines
TNF- and IFN- (Fig. 2, e and g). In
contrast, TSA-TRAIL tumors showed a scanty reactive infiltrate (Fig. 2, b and d), albeit with a distinct presence of
lymphocytes associated with a moderate or scarce presence of adhesion
molecules on the endothelial cells, and a limited expression of
proinflammatory cytokines (Fig. 2, f and h). At
day 7, lymphocytes interacting with TSA-TRAIL cells displayed
ultrastructural features of cells undergoing apoptosis (Fig. 2, i and j).
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B6 mice (H-2b) differ from BALB/c mice at
both multiple minor alloantigens and the full MHC. In these recipients,
106 TSA-pc were promptly rejected (Fig. 3A), whereas
106 TSA-TRAIL cells grew progressively in all
mice and formed 4- to 9-mm tumor masses that later regressed in 79%.
In three mice, TSA-TRAIL cells grew progressively and overcame the
survival threshold. All mice rejected 105 TSA-pc
cells, whereas a similar dose of TSA-TRAIL cells grew progressively,
but overcame the survival threshold in two mice only (Fig. 3B). The unchanged expression of
H-2Kd, H-2Dd, and
H-2Ld glycoproteins by TSA-TRAIL tumors in these
mice shows that their ability to overcome histocompatibility barriers
is not due to a reduction in MHC glycoproteins (Fig. 3C).
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). Adhesion molecules were strongly expressed by blood vessels. An
intense positivity for proinflammatory cytokines and iNOS was also
detected. Three days after challenge, the reactive infiltrate invading
the TSA-pc inoculum area was so massive that only a few scattered
TSA-pc cells could be observed close to areas of ischemic-coagulative
necrosis. This quick rejection prevented counting of the infiltrating
cells and evaluation of cytokine expression. The lytic response to
H-2d alloantigens primed by TSA-TRAIL and TSA-pc
rejection in B6 mice was evaluated 2 wk after tumor challenge.
Rejection of TSA-pc cells primed a strong lytic activity against
H-2d cells. That of TSA-TRAIL did not. The
similar cytolytic response to H-2k cells of mice
that rejected TSA-pc and TSA-TRAIL suggests that a nonspecific
immunosuppression due to factors released by TSA-TRAIL is not the
reason for the diminished reaction to H-2d cells
(Table IV).
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The ability of TSA-TRAIL cells to escape lysis by alloactivated T
lymphocytes was evaluated in 4- and 48-h cytotoxicity assays. DBA/2 and
B6 T lymphocytes were first stimulated with spleen cells from
allogeneic mice. B6 anti-BALB/c lymphocytes killed TSA-pc
moderately well in a 4-h 51Cr release assay, and
much better in a 48-h [3H]TdR release assay.
TSA-TRAIL cells were more resistant to lysis in both assays. In the
48-h assay, they were killed 90% less than TSA-pc (Table V).
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and data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Strong cytolytic responses directed to BALB/c histocompatibility Ags are poorly effective against TSA-TRAIL cells. Their resistance is particularly evident in the 48-h test, where a prolonged interaction between effector and TSA-TRAIL cells takes place. Moreover, an overnight interaction with TSA-TRAIL cells induces the apoptotic death of a significant number of specifically activated T lymphocytes. Apoptosis of reacting T cells appears to be directly due to the TRAIL on the membrane, since it is markedly diminished by anti-TRAIL IgG and by caspase-1 inhibitors. These findings, coupled with the evidence of apoptotic lymphocytes revealed by ultrastructural observations ex vivo, suggest that induction of apoptosis in activated lymphocytes that interact with TSA-TRAIL is an important mechanism by which they escape T cell reactivity. In effect, by interacting with a series of signaling receptors, TRAIL induces the apoptosis of many cells, including lymphocytes (9, 24, 25, 26). The apoptosis-inducing ability of TSA-TRAIL cells appears to be mainly due to their membrane-expressed TRAIL, since supernatants from TSA-TRAIL or TSA-pc cultures added to alloactivated lymphocytes do not influence their survival (data not shown).
A possible autocrine-positive loop in TSA-TRAIL cells and a direct survival advantage deriving from TRAIL membrane expression cannot be formally ruled out. However, the similarity between TSA-TRAIL and TSA-pc in their release of factors, MHC molecule expression, and growth pattern in vitro and in nu/nu mice seem to preclude a major effect of TRAIL on TSA cell behavior. The ability of TSA-TRAIL cells to evade strong T lymphocyte-dependent immune responses is somewhat similar to that of tumor cells that naturally express CD95L (14, 27, 28, 29). Their inability to elicit the neutrophil-dependent reaction leading to tumor rejection may be the key to the different in vivo behavior of CD95L and TRAIL-engineered cells (30, 31). CD95L, besides its ability to induce apoptosis of lymphoid cells and angiogenic activity (32), may well enhance endothelial cell expression of adhesion molecules and promote the neutrophil extravasation that leads to the rejection of tumor cells. However, immunohistochemical analysis revealed that TSA-TRAIL cells injected into syngeneic animals also activate endothelial cells, induce VCAM-1 and endothelial leukocyte adhesion molecule-1 expression, and favor development of the tumor vascular network. The accelerated rejection following CD95L transduction may rest on its quantitative expression (33). Overexpression may determine local endothelium activation (32) strong enough to lead to marked neutrophil infiltration (30, 31). However, the different in vivo behavior of CD95L- and TRAIL-engineered tumors may be due to the diversities of these two ligands. TRAIL is 28% identical to CD95L and 23% identical to both TNF and lymphotoxin (1, 2) and acts on a different set of death-signaling receptors expressed by many normal and transformed cell types (4, 5, 6, 7, 8, 34). A complex modulation of multiple signaling and decoy receptors regulates the ability of TRAIL expressed by engineered tumors as well as by normal and neoplastic cells to suppress an immune response by delivering apoptotic signals (6, 11, 34). The susceptibility of lymphocytes to TRAIL-induced apoptosis changes in various situations (35, 36, 37). Data on the modulation of TRAIL receptor expression on lymphocyte activation are not yet available, and no correlation between receptor expression and the level of cell sensitivity to TRAIL apoptosis is evident (11, 34).
TRAIL-death receptors form a relatively newly characterized immune regulatory system, several aspects of which are not yet defined, though the present data offer an insight into its efficacy on genetically engineered tumor cells. Novel therapeutic strategies aiming to both hamper tumor escape from immune reactivity and facilitate allograft evasion from immune rejection should take it into serious account.
By contrast, the natural expression of TRAIL and other death ligands by tumor cells probably has a much less devastating inhibitory effect. Their expression is likely to be lower and extremely carefully regulated by cytokines and other environmental signals. Moreover, the presence of decoy receptors is another way to restrict their death potential. Cytokines regulating the expression of death ligands can also protect lymphocytes from tumor-induced apoptosis. These and other natural guards allowing lymphocytes to survive in the presence of TRAIL can also explain the rejection of TSA-TRAIL cells by fully allogeneic mice, despite the marked TRAIL expression on their cell membrane.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mirella Giovarelli, Department of Clinical and Biological Sciences, University of Torino, Ospedale S. Luigi Gonzaga, 10043 Orbassano, Italy. E-mail address:
3 Abbreviations used in this paper: TRAIL, TNF-related apoptosis-inducing ligand; APO-2L, APO-2 ligand; B6, C57BL/6 mice; CD95L, CD95 ligand; iNOS, inducible NO synthetase; ZVAD-fmk, Z-Val-Ala-Asp (O-methyl)-fluoromethyl ketone; YVAD-cmk, Y-Val-Ala-Asp (O-methyl)chloromethyl ketone; TSA-pc, TSA parental cells.
Received for publication May 24, 1999. Accepted for publication August 18, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7:813.[Medline]
induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res. 58:2832.B. Immunity 7:831.[Medline]
B pathway. Immunity 7:821.[Medline]
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