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Department of
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Medicine and
Immunology, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206; Departments of
Medicine,
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Immunology, and the
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Cancer Center, University of Colorado Medical School, Denver, CO 80262; and
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Department of Medicine and Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fas-ligand. Because
TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar
manner as TNF- and Fas ligand, we asked whether E1A expression might
sensitize cells to lysis by TRAIL. To test this hypothesis, we examined
TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4)
cells that expressed E1A following either infection with Ad5 or stable
transfection with Ad5-E1A. E1A-transfected A2058 (A2058-E1A) or H4
(H4-E1A) cells were highly sensitive to TRAIL-induced killing, but
Ad5-infected cells expressing equally high levels of E1A protein
remained resistant to TRAIL. Infection of A2058-E1A cells with Ad5
reduced their sensitivity to TRAIL-dependent killing. Therefore, viral
gene products expressed following infection with Ad5 inhibited the
sensitivity to TRAIL-induced killing conferred by transfection with
E1A. E1B and E3 gene products have been shown to inhibit TNF-- and
Fas-dependent killing. The effect of these gene products on
TRAIL-dependent killing was examined by using Ad5-mutants that did not
express either the E3 (H5dl327) or E1B-19K
(H5dl250) coding regions. A2058 cells infected with
H5dl327 were susceptible to TRAIL-dependent killing.
Furthermore, TRAIL-dependent killing of A2058-E1A cells was not
inhibited by infection with H5dl327. Infection with
H5dl250 sensitized A2058 cells to TRAIL-induced killing,
but considerably less than H5dl327-infection. In
summary, expression of Ad5-E1A gene products sensitizes cells to
TRAIL-dependent killing, whereas E3 gene products, and to a lesser
extent E1B-19K, inhibit this effect. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One possible explanation for the lack of oncogenicity of Ad in humans
is the capacity of E1A to sensitize cells to destruction by components
of the host cellular immune response (6, 7, 8, 9). The
expression of E1A sensitizes cells to lysis by components of the
cellular antitumor immune response, including NK cells, activated
macrophages, and CTL (6, 7, 8, 9). These effector cells kill
target cells by several mechanisms including the elaboration of
secreted proteins, such as TNF- and perforin, or by the interaction
of Fas ligand on effector cells with Fas on target cells. The
expression of E1A in epithelial or fibroblastic cells induces an
increased susceptibility to lysis by TNF-, perforin, and Fas ligand
(10, 11, 12).
Recent studies have characterized a new member of the TNF family of
cytokines, the TNF-related apoptosis-inducing ligand (TRAIL) (13, 14). TRAIL interacts with receptors that are distinct from the
receptors for Fas ligand and TNF-. To date, five receptors have been
shown to bind TRAIL. The binding of TRAIL to either TRAIL-R1 (death
receptor 1) or TRAIL-R2 induces apoptosis (15, 16, 17). In
contrast, the binding of TRAIL to TRIAL-R3, TRAIL-R4, or
osteoprotegerin does not induce apoptosis (15, 16, 18, 19, 20, 21). TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and
osteoprotegerin are all members of the TNF-receptor family. The
cytoplasmic domains of TRAIL-R1 and TRAIL-R2, like those of the
receptors for Fas ligand and TNF-, contain cytoplasmic death domains
and likely use the same or similar pathways of caspase activation to
induce apoptosis (22). In contrast, TRAIL-R3 and TRAIL-R4
lack cytoplasmic death domains, and osteoprotegerin is a secreted
protein. In contrast to TNF- and Fas ligand, which are expressed
primarily by cells of the immune system, TRAIL is produced by a wide
variety of cell types (22). TRAIL preferentially induces
apoptosis of certain tumor cell lines and virally infected cells,
whereas nontransformed cells are generally resistant to TRAIL-induced
killing (23, 24). TRAIL also contributes to the
cytotoxicity mediated by CD4+ T cells and
monocytes (25).
Based on the ability of TRAIL to selectively kill virally infected
cells and the similar molecular mechanisms of TRAIL-, Fas-, and
TNF--induced apoptosis, we postulated that E1A expression in
Ad-infected and E1A-transfected tumor cells might also sensitize cells
to TRAIL-induced killing. To test this hypothesis, we determined the
effect of E1A expression on TRAIL-induced killing of A2058 and H4
cells. A2058 cells, a human melanoma cancer cell line, and H4, a human
fibrosarcoma cell line, were chosen because they are resistant to
TRAIL-induced killing and are permissive for infection with Ad5
(26). We found that the expression of E1A gene products
sensitizes human tumor cells to TRAIL-dependent killing. The ability of
E1A to sensitize cells to TRAIL-induced killing following Ad5 infection
was inhibited by E3 gene products, and to a lesser extent E1B-19K.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A2058 is a human melanoma cell line. H4 is a human fibrosarcoma cell line. A2058-E1A (also known as 1A558C8) and H4-E1A (also known as P2AHT2A) are Ad5-E1A-transfected A2058 and H4 cells, respectively (27). Cell lines were maintained in DMEM supplemented with 5% calf serum, glucose (15 mM), antibiotics, and glutamine. The absence of Mycoplasma in the cell lines was established by using the Mycotect Assay (Life Technologies, Gaithersburg, MD).
Viruses
H5dl327 is an Ad5 mutant virus that does not express any E3 proteins (28). H5dl250 is an Ad5 mutant that does not express the E1B-19K protein (29). Wild-type Ad5 and H5dl327 were grown in A549 cells. H5dl250 was grown in 293 cells. Each virus was titered by plaque assay using the cell line in which it was grown.
TRAIL cytolysis assays
Target cells were infected with the different Ad (multiplicity of infection = 100) for 16 h and labeled with 51Cr (100 mCi/ml for 1 h; 1 Ci = 37 gBq). Initial studies showed that equivalent amounts of E1A were expressed following infection of cells at a multiplicity of infection of 100 with wild-type or mutant forms of Ad5 (data not shown). Target cells (1 x 104 cells) were then incubated with different concentrations of recombinant human TRAIL (R&D Systems, Minneapolis, MN). After a 16-h incubation at 37°C in 5% CO2, half of the supernatant from each well was harvested and counted in a gamma counter. TRAIL-dependent killing was determined by calculating the percentage of TRAIL-induced release of radiolabel from target cells as described (9). The results shown represent the mean ± SEM of at least four separate experiments. The mean percentage spontaneous release from all types of target cells was <30%. The significance of the differences in TRAIL-induced killing of control and infected cell lines was estimated using Student’s t test.
Western analysis
For quantitation of E1A proteins, 60-mm plates of Ad-infected or E1A-transfected A2058 or H4 cells were lysed in RIPA buffer (1% Nonidet P-40, 0.5% deoxycholate, 0.1% SDS, 50 mM Tris, pH 7.4, 150 mM NaCl), and protein concentrations of RIPA supernatants were determined by the bicinchoninic acid protein assay (Pierce, Rockford, IL). An equal amount of protein from each cell lysate was separated on 10% SDS polyacrylamide gels and electrophoretically transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA). Membranes were blocked in 5% nonfat milk solution and incubated with the anti-E1A mAb, M73 (supplied by E. Harlow, Massachusetts General Hospital, Charleston, MA) for 1 h (30). Following several washes with PBST (PBS with 0.05% Triton X-100), membranes were incubated for 1 h with rabbit anti-mouse IgG Ab (Cappel, Durham, NC) and washed extensively with PBST. The E1A protein was then visualized as per manufacturer instructions using the Renaissance Chemiluminescence Kit (DuPont-NEN, Boston, MA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether E1A sensitized cells to TRAIL, cytolysis
assays were performed on parental and E1A-transfected melanoma (A2058,
A2058-E1A) and fibrosarcoma (H4, H4-E1A) cells. In agreement with prior
reports, we found that both H4 and A2058 cells were resistant to
TRAIL-induced killing (Fig. 1
). The
resistance of A2058 or H4 cells to TRAIL-induced killing was abrogated
by the stable transfection with E1A (Fig. 1). Cell lines have been
considered sensitive to TRAIL-induced killing if incubation of 300
ng/ml of recombinant TRAIL results in >20% killing (22, 26). We found that the addition of 12.5–25 ng/ml of TRAIL
killed >25% of A2058-E1A and H4-E1A cells. The ability of E1A
expression to sensitize tumor cells to TRAIL-dependent killing was not
restricted to melanoma or fibrosarcoma cells. TRAIL-dependent killing
of breast cancer and cervical cancer cell lines was also increased by
stable E1A-transfection (data not shown). Next, we ascertained whether
the expression of E1A gene products following Ad5 infection would also
induce TRAIL-dependent killing. In contrast to transfection with E1A,
infection of A2058 or H4 cells with Ad5 did not confer sensitivity to
TRAIL-dependent killing (Fig. 1).
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The ability of E1A gene products to increase the susceptibility to
lysis by NK cells and macrophages is dependent on the level of E1A
expressed (11). Prior studies from our laboratory showed
that equivalent amounts of E1A protein are expressed in Ad5- compared
with E1A-transfected H4 cells (6). However, it was
possible that the levels of E1A produced following Ad5-infection of
A2058 cells were insufficient to induce sensitivity to TRAIL-dependent
killing. To test this possibility, the levels of E1A oncoprotein in
Ad5-infected and E1A-transfected A2058 cells were compared. Western
blot analysis of cell lysates demonstrated that the amounts of E1A in
Ad5-infected and E1A-transfected A2058 cells were comparable (Fig. 2). Therefore, the resistance of
Ad5-infected A2058 or H4 cells to TRAIL-dependent killing could not be
explained by quantitative differences in the expression of E1A gene
products.
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Expression of E1A gene products in immortalized cells induces
susceptibility to NK cell lysis. In contrast, infection of human cells
with Ad does not render the cells susceptible to NK cell lysis
(6). Thus, it was possible that the transient expression
of E1A gene products following Ad5-infection was insufficient to induce
sensitivity to TRAIL-dependent killing. Alternatively, other viral gene
products produced following Ad infection could be responsible for the
inability of Ad5 infection to sensitize cells to TRAIL-dependent
killing. To test the latter possibility, we examined whether
Ad5-infection inhibited TRAIL-dependent killing of A2058-E1A cells. As
shown in Fig. 3, Ad5-infection of
A2058-E1A cells reduced the killing by TRAIL compared with that
obtained with uninfected cells.
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The effect of these gene products on TRAIL-dependent
killing was examined by using mutant strains of Ad5 that did not
express either the E3 (H5dl327) or E1B-19K
(H5dl250) coding regions. A2058 cells infected with
H5dl250 (which does not express E1B-19K, but does express
E1A and E3 proteins) resulted in a small increase in TRAIL-induced
killing compared with uninfected cells (Fig. 4A). In contrast, infection of
A2058 cells with H5dl327 (which does not express E3
proteins, but does express E1A and E1B-proteins) increased the
sensitivity of A2058 cells to TRAIL-dependent killing to a level that
was similar to that observed with A2058-E1A cells (Fig. 4A).
Furthermore, infection of A2058-E1A cells with H5dl327 did
not inhibit their TRAIL sensitivity (Fig. 4B). The ability
of H5dl250 infection to block TRAIL-induced killing in
A2058-E1A cells could not be assessed because infection of these cells
with H5dl250 produced a high spontaneous release of
51Cr. In total, these data indicated that E3
proteins inhibited the ability of E1A gene products, produced following
transfection or infection, to sensitize cells to TRAIL-dependent
killing. The E1B-19K protein inhibited TRAIL-induced killing to a
lesser extent than E3 gene products.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
Similar data were obtained with E1A-transfected breast cancer and
cervical cancer cells (data not shown). These data are similar to
reports that E1A gene products sensitize human and murine cells to
TNF- and Fas-dependent killing (10, 11, 12). However, E1A
gene products do not always sensitize human or rodent cells to lysis by
immune mediators or effector cells (8, 31, 32, 33).
Furthermore, the molecular basis for the increased susceptibility of
E1A-expressing cells to TNF- and Fas-dependent killing is unknown.
Therefore, the ability of E1A to sensitize human tumor cells to
TRAIL-dependent killing needed to be directly ascertained.
TRAIL-dependent killing of A2058 cells was also increased by the
expression of E1A gene products produced in the context of
Ad-infection. However, because E1B and E3 gene products block
TRAIL-induced killing, this effect of E1A could not be detected by
infection of A2058 cells with wild-type Ad5. For example, in contrast
to A2058-E1A cells, A2058 cells infected with wild-type Ad5 were
resistant to lysis by TRAIL (Fig. 1A). This difference
between Ad5-infected and E1A-transfected cells was not due to
differences in E1A expression. A2058-E1A cells and A2058 cells infected
with Ad5 expressed equivalent levels of E1A oncoprotein (Fig. 2).
Similar to results on A2058 cells, Ad5-infected H4 cells also were
resistant to TRAIL-dependent killing, despite high levels of E1A
expression (Fig. 1B, and Ref. 6). Proteins
encoded by the E3 regions were predominately responsible for the
resistance of Ad5-infected A2058 cells to lysis by TRAIL. A2058 cells
infected with H5dl327 (which does not express E3 proteins,
but does expresses E1B proteins) were nearly as sensitive to
TRAIL-dependent killing as A2058-E1A cells (Fig. 4A).
TRAIL-dependent killing was also blocked by E1B-19K, although they were
less effective than proteins encoded by the E3 region. Thus,
H5dl250 (which does not express E1B-19K, but expresses E3
proteins) infection of A2058 cells increased TRAIL-dependent killing,
but to a lesser extent than infection with H5dl327 (Fig. 4A). Furthermore, E1B gene products failed to inhibit
killing of A2058-E1A cells following infection with H5dl327
(Fig. 4B). In contrast, TRAIL-dependent killing of A2058-E1A
cells was blocked following infection with Ad5 (expresses E1B and E3;
Fig. 4). In total, these studies indicate that E3 gene products were
more effective at inhibiting TRAIL-dependent killing than the E1B-19K
proteins.
Ad encode numerous proteins that facilitate the evasion of the host
immune response and contribute to viral persistence (34).
Several proteins encoded by the E1B and E3 regions have been previously
shown to inhibit TNF- and Fas-induced killing and thus are
candidates to inhibit TRAIL-induced killing (35, 36, 37). For
example, the E1B 19K protein, which is functionally homologous to the
protoncogene Bcl-2, inhibits the activation of Procaspace-8 (FLICE)
(36). In addition, the E3 10.4K and 14.5K proteins (also
known as E3-RID) bind to and reduce the surface expression of Fas
(39, 40). Another E3 protein, E3–14.7K, blocks apoptosis
by its ability to bind and alter the function of proteins involved in
NF-
B-apoptosis regulatory pathway (41). Studies are
ongoing to determine the molecular mechanism by which the E1B and E3
proteins inhibit TRAIL-induced killing.
Other adenoviral proteins are implicated in the evasion of host immune
responses. Certain Ad-encoded proteins inhibit the biological
activities of IFNs and CTL recogntion of Ad-infected cells
(42, 43, 44). Therefore, it is puzzling that Ad rarely cause
disseminated infections and do not appear to be oncogenic in humans,
despite their well-described ability to transform human cells (4, 45, 46, 47, 48). We speculate that the biological behavior of Ad in
humans is best explained by the incomplete inhibition of the host
cellular innate (NK cells, macrophages) and acquired (T cell) immune
responses by adenoviral immunomodulatory proteins during infection as
well as minimal effects of these viral proteins on immune defenses
following viral transformation. For example, Ad-transformed human cells
are selectively killed by resting and IFN-activated NK cells
(6, 49). In contrast, Ad-infected human cells are only
selectively killed by IFN-activated NK cells (33, 50). In
mouse models, a robust CTL response is induced following injection of
E1A-expressing tumor cells, and, as a result, CTL are highly effective
at eliminating Ad-transformed cells in vivo (51, 52). We
speculate that an effective CTL response would also be generated
against E1A-expressing, Ad-transformed cells in humans. CTL are also
induced following Ad-infection (53, 54, 55). However, CTL
recognition of Ad-infected cells appears to be partially subverted by
the Ad-E3-19K protein, a protein that is usually not expressed in
Ad-transformed cells (44, 56, 57). The inhibition of
TRAIL-dependent killing by the E3 proteins provides another mechanism
that could enable Ad to escape innate immunity and favor viral
persistence. However, our data suggest that TRAIL-dependent killing
would be highly effective in eliminating E1A-expressing human cells
that became immortalized following a transforming viral infection. For
example, E1A-transfected A2058 and H4 cells and A2058 cells infected
with H5dl327 (which express the E1A and E1B proteins) were
highly susceptible to TRAIL-dependent killing (Fig. 4). Therefore, we
predict that Ad-transformed, E1A and E1B expressing human cells would
also be highly sensitive to TRAIL-dependent killing. Thus, the
immunomodulatory proteins encoded by Ad may prevent a rapid sterilizing
immune response and favor viral-persistence, but are insufficient to
fully evade host immunity. Furthermore, in Ad-transformed cells, these
immunomodulatory proteins are either not present (E3) or are
ineffective (E1B) in blocking killing by host effector killer
mechanisms (5, 58).
The results from this study are also highly relevant in the selection of the optimal adenovirus mutant to be used in the treatment of human malignancy. Phase I clinical trials are presently underway using ONYX-015, an Ad-mutant that does not express the E1B-55K protein (59). E1B-55K partially inhibits the p53-dependent apoptosis induced by E1A-expression (60). The deletion of E1B-55K may enable ONYX-015 to replicate and induce apoptosis in p53-deficient human cancer cells but may leave normal (p53 positive) cells intact (61, 62, 63). For several reasons, we speculate that adenoviral mutants that contain deletions in both the E1B and E3 coding regions would be superior to ONYX-015 for the treatment of human malignancies. The first reason is that immune mechanisms likely participate in mediating tumor regression following Ad-infection. For example, several reports indicate that the ability of E1A to reduce tumorigenicity is dependent on NK and T cells (64, 65, 66, 67). The ability of E1A to sensitize cells to immune-mediated apoptosis is independent of p53 (66, 68 , insensitive to E1B-19K. The second reason is that prior studies indicate that combining chemotherapeutic agents with ONYX-015 is more effective in mediating tumor destruction than either agent alone (63). This effect is likely due to the ability of E1A to sensitize cells to apoptosis induced by chemotherapeutic agents (69). However, in E1A-expessing tumor cells, the p53-dependent induction of apoptosis induced by chemotherapeutic agents is also inhibited by E1B-19K (68). A third reason is that recent studies indicate that TRAIL may be useful in the treatment of human malignancies. By inducing the expression of TRAIL-R1 and TRAIL-R2, chemotherapeutic agents such as etoposide synergize with TRAIL to mediate tumor cell apoptosis (70). Studies reported here indicate that TRAIL-resistant tumors can be sensitized by the expression of E1A gene products. In contrast, E3 gene products block TRAIL-induced killing of E1A-expressing tumor cells. The use of mutant Ad that have deleted both E1B (19K and 55K) and E3 gene products may optimize the synergistic interactions involving chemotherapeutic agents, TRAIL and E1A. For all these reasons, we believe that mutant adenoviruses that contain deletions of both the E1B and E3 open reading frames would be more effective in the treatment of human malignancies than ONYX-015, regardless of whether the virus was used alone or in combination with other chemotherapeutic agents. Studies are ongoing using murine models to directly test this hypothesis.
In summary, we show that the expression of E1A gene products sensitizes tumor cells to TRAIL-dependent killing. The gene products of the E3 region, and to a lesser extent E1B1-19K, inhibit this effect. Studies are ongoing to determine the molecular basis for the ability of E1A gene products to sensitize cells to TRAIL-dependent killing.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. John M. Routes, National Jewish Center for Immunology and Respiratory Medicine, Department of Medicine, 1400 Jackson Street, Denver, CO 80206.
3 Abbreviations used in this paper: Ad, adenovirus; TRAIL, TNF-related apoptosis-inducing ligand.
Received for publication May 16, 2000. Accepted for publication July 20, 2000.
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), Ad5-infected-A2058 (•), or
A2058-E1A (
) cells. B, TRAIL-induced killing of H4
(
) A2058 cells. B,
TRAIL-induced killing of A2058 (