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CUTTING EDGE |
*
Department of Dermatology and
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and Discussion References |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and Discussion References |
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CTLs target tumors through recognition of a ligand consisting of a self MHC class I molecule and peptide Ag generally derived from proteins synthesized within the tumor cell (2, 3). However, for CTL induction and expansion to occur, the antigenic ligand must be presented to CTLs in the appropriate context of costimulation usually provided by professional APCs (4). Delivery of exogenous Ag to the endogenous MHC class I restricted processing pathway of professional APCs is a critical challenge in cancer vaccine design. Ag delivery strategies currently under development include immunization with defined peptides (5), particulate proteins capable of accessing the class I pathway of professional APCs in vivo (6), heat shock proteins isolated from tumor cells (7), or adoptive transfer of Ag-loaded APCs (8, 9, 10, 11, 12). In addition, recent studies suggest that DNA vaccines encoding tumor Ags delivered by viral vectors or liposomes, or as naked DNA, can induce potent antitumor immunity (13, 14, 15).
In addition to the challenge of Ag delivery, most current tumor immunization strategies depend on the identification and production of appropriate tumor Ags. To overcome this limitation, tumor cells themselves may be used as immunogens. It is likely that a tumor cell expresses a set of tumor-specific peptide-MHC complexes recognized by T cells. However, progressive tumors are generally nonimmunogenic at least in part because they are incapable of providing costimulation. Engineering tumor cells to provide APC function could potentially result in polyvalent immunization to multiple tumor-specific epitopes, while obviating the need to identify specific tumor Ags. A variety of strategies are being developed to provide "APC-like" function to tumor cells primarily by transfecting tumor cells with genes encoding costimulatory molecules or cytokines (reviewed in 16 . However, recent studies demonstrate that the in vivo generation of immune responses against tumor cells generally occurs through cross-priming, with tumor Ag presentation being dependent on bone marrow-derived APCs of the host (17). The mechanism by which tumor Ags are taken up and presented by host APCs remains unclear.
Dendritic cells (DCs)3 are the most potent APCs identified thus far, and adoptive transfer of Ag-loaded DCs can induce effective CTL-dependent antitumor immunity (8, 9, 10, 11, 12). Recent advances have made it possible to obtain significant quantities of dendritic cells from bone marrow or peripheral blood-derived precursors (18, 19). The efficacy of DC adoptive transfer therapies suggests that in vitro manipulated DCs maintain essential APC functions including appropriate trafficking and localization, and Ag presentation in the context of requisite costimulatory signals for T cell induction. DC adoptive transfer therapies are currently limited by their dependence on in vitro Ag loading and the availability of appropriate, defined tumor Ags.
In a novel and promising approach to tumor cell-based immunization, Guo et al. (20) have shown that the fusion of activated B cells to tumor cells produces a potent immunogen, capable of inducing tumor-specific tumor immunity. Like B cell-tumor cell fusion products, the product of DC-tumor cell fusions is also a potent immunogen (21). The broad applicability of APC-tumor cell fusion strategies to human tumor immunotherapy will likely depend on both the capacity to generate and select immunogenic APC-tumor cell hybrids and the stability of their expression of the factors critical to immunogenicity. Here we show that short term coculture of DCs and tumor cells, with or without prior fusion, results in a potent immunogen capable of inducing CTL-mediated protective antitumor immunity and the regression of established tumors. Our results suggest that the immunogenicity of this cellular vaccine is dependent on the physical interaction of DCs and tumor cells before injection. The implications of these findings for human tumor immunotherapy and vaccine design are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and Discussion References |
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Female C57BL/6 mice, 5 to 8 wk old, were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed at the Central Animal Facility of the University of Pittsburgh. B16 is a C57BL/6-derived melanoma (H-2b) (American Type Culture Collection (ATCC), Rockville, MD). 3LL is a C57BL/6-derived lung carcinoma (22). Cell lines were maintained in Dulbecco’s modified Eagle’s medium containing 10% FCS and antibiotics.
Antibodies
mAbs used to deplete cell subsets were prepared from the hybridomas GK1.5 (anti-CD4, ATCC TIB 207), 2.43 (anti-CD8, ATCC TIB 210), 30-H12 (anti-Thy-1.2, ATCC TIB 107), B220 (anti-B cell surface glycoprotein, ATCC TIB 146).
Preparation of DCs
DCs were prepared from bone marrow as described (9), with slight modifications. Briefly, bone marrow cells were depleted of lymphocytes and cultured at 5 x 105 cells/ml in 10% FCS-containing RPMI 1640 (Irvine Scientific, Santa Ana, CA) with granulocyte-macrophage-CSF (103 U/ml; Sigma Chemical Co., St. Louis, MO). Loosely adherent cells were collected on day 6 for fusion or coculture. DCs obtained by these methods expressed both CD86 (B7.2) and class II MHC Ags as determined by flow cytometry (9, 11) (data not shown).
Fusion or coculture of DCs and tumor cells
Day 6 DCs were fused with B16 or 3LL cells at a ratio of 6:1 using polyethylene glycol (PEG) warmed to 37°C as described (23). After PBS washes, fused cells were cultured overnight at 37°C in RPMI 1640 (10% FCS) containing granulocyte-macrophage-CSF. Cocultured groups were identically prepared except that polyethylene glycol (PEG) was omitted. Flow cytometry was used to assess the efficiency of cell association. DCs were labeled with the fluorochrome DiIC18(5) (1 µg/ml final concentration, EX 644/EM 663; Molecular Probes, Inc., Eugene, OR), and tumor cells were labeled with DiOC16(3) (2 µg/ml final concentration, EX 484/EM 501; Molecular Probes) by incubation of cells with either fluorochrome for 30 min at 37°C in PBS. These dyes uniformly label the plasma membrane and do not transfer between intact membranes (Molecular Probes). Labeled cells were extensively washed, fused or mock-fused (i.e., cocultured), and allowed to incubate overnight in RPMI 1640 at 37°C. Harvested cells were fixed in 2% paraformaldehyde before analysis using a Becton Dickinson FACStarPlus with argon/HeNe dual laser (Becton Dickinson Immunocytometry Systems, San Jose, CA).
Cytotoxicity assay
Splenocytes (30 x 106), harvested from
mice 7 days after the last immunization (see below), were restimulated
by coculture with irradiated B16 or 3LL cells (7.5 x
106, 20,000 rad) for 5 days. After this time, cytotoxicity
assays were performed as described (9). Briefly, target cells were
labeled by incubation in RPMI with 51Cr (100 µCi; NEN,
Boston, MA) for 18 h at 37°C, washed, and then cocultured at
2 x 104 target cells/well for 4 h at 37°C in
96-well round-bottom plates (200 µl/well) with effector cells at the
ratios given in Table I
. In some cases,
effector cells were depleted of CD4+, CD8+, or
Thy-1.2+ by incubation with mAbs against these markers plus
complement. Collected and counted were 100 µl of supernatants from
triplicate cocultures. The SE of the mean of triplicate cultures was
not >5%. Data points are expressed as the mean percent specific
release of 51Cr from target cells and were calculated as
described (9).
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On day 0, C57BL/6 mice were immunized s.c. in both lower flanks (100 µl/side) with DCs alone (1.7 x 106 per mouse), tumor cells (B16 or 3LL, 3 x 105 per mouse) alone, fused DCs and tumor cells (B16 or 3LL, 6:1 (i.e., 1.7 x 106 DCs: 3 x 105 tumor cells per mouse)), mock-fused (i.e., cocultured) DCs and tumor cells (B16 or 3LL, 6:1), identical numbers of DCs and tumor cells (B16 or 3LL, 6:1) injected together without prior coculture, identical numbers of DCs and tumor cells cocultured (B16 or 3LL, 6:1) in Transwell plates (Costar, Cambridge, MA) to prohibit direct cell contact and then injected, supernatants from the same Transwell cocultures (not shown), or PBS. Cells were irradiated (20,000 rad) and resuspended in PBS before injection. Seven days later, mice were challenged with tumor cells (B16 or 3LL; 5 x 104/mouse/200 µl at 100 µl/side) in PBS delivered by intradermal injection to the midflanks bilaterally. Surviving mice that became moribund were killed according to animal care guidelines of the University of Pittsburgh Medical Center. Survival is recorded as the percentage of surviving animals.
Immunotherapy
Mice were challenged intradermally in the midflanks bilaterally with 3LL cells at 5 x 104 cells/mouse. On day 7 (average tumor size, 5.9 mm2/mouse, SE ± 0.8), mice were immunized by s.c. injection bilaterally in the lower flanks with individual or combinations of DCs and tumor cells (listed above). A second injection was given on day 10. Survival was followed as described above.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and Discussion References |
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A; tumor
cells, lower left, Fig. 1B) compared with
unstained controls (not shown). In contrast, after 24 h of
culture, cells from both cocultured and fused groups showed a high
degree of association, with most cell conjugates expressing both DiIC18
(5) and DiOC16(3) (Fig. 1, C and D).
Importantly, most tumor cells were associated with DCs (Fig. 1, C and D). Morphologically, both fused and
cocultured groups demonstrated distinct cell aggregates that could not
be easily disrupted (not shown). The capacity of DCs to cluster with T
cells and other cell types has been previously described (24).
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). Similarly,
splenocytes from mice immunized with 3LL-DC fusions demonstrated
specific lytic activity against 3LL (Table I). Importantly, effector
splenocytes from mice immunized with cells from tumor-DC cocultures
that had not undergone fusion demonstrated similar CTL-mediated
tumor-specific lytic activity (Table I). Depletion of CD8+
or Thy-1+ but not CD4+ cell subsets from
effector populations using mAbs eliminated lytic activity and
demonstrated that lysis depended on Thy-1+ CD8+
T cell subsets characteristic of MHC class I restricted CTL effector
cells (Table I). The effect of this immunization strategy on NK cell
activity in general was not directly addressed. In contrast to
immunizations with DC-tumor cell fusions or cocultures, identical
numbers of DCs and tumor cells that had not been cocultured but were
injected together at a 6:1 ratio did not induce tumor-specific lytic
activity (Table I, coinjection groups), suggesting that in vitro
coincubation of DCs with tumor cells was necessary for immunogenicity.
Furthermore, injection of DCs alone that had been cocultured with tumor
cells at identical ratios and cell densities, but separated by a porous
membrane barrier to prevent direct DC-tumor cell contact, did not
induce lytic activity (Table I), suggesting that tumor-specific
immunity was not mediated by the transfer of soluble factors from tumor
cells to DCs in these in vitro cocultures.
To determine the capacity of DC-tumor conjugates to induce antitumor
immunity in vivo, groups of naive mice were immunized s.c. with
irradiated DC-tumor cell conjugates without adjuvant and then
challenged 7 days later by intradermal injection of the tumor cells in
the flanks bilaterally. Mice immunized with irradiated cells from
DC-B16 fusions or cocultures were completely protected from lethal
challenge with B16 tumor cells (Fig. 2A). Groups of mice
injected with PBS, similar numbers of irradiated DCs or tumor cells
alone, or irradiated DCs from membrane-separated Transwell DC-tumor
cell cultures were not protected and uniformly developed lethal tumors
(Fig. 2A). Importantly, mice immunized with DCs and
tumor cells that were injected together without prior coculture were
not protected (Fig. 2B). This is in agreement with
previously published results (20, 21). Similarly, immunization with
irradiated cells from DC-3LL fusions or cocultures protected mice from
challenge with 3LL, while s.c. injection of irradiated DCs or tumor
cells alone or irradiated DCs from membrane-separated Transwell
DC-tumor cell cocultures were ineffective (Fig. 2C).
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A). All mice
immunized with irradiated DC-3LL fusion products survived for at least
72 days and had no evidence of tumor when the experiment was terminated
(Fig. 3A). Immunization with cocultured cells from
mock fusions prolonged survival in most mice and resulted in complete
regression in 75% of the animals treated. Furthermore, mice that
demonstrated complete tumor regression were rechallenged 3 mo later by
i.v. injection of tumor cells. Tumors did not develop in mice that
received fusion products or coculture products (Fig. 3B), demonstrating that the antitumor immunity
induced by these vaccines was long lasting.
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Our studies demonstrate that PEG-mediated fusion is not required
for immunogenicity. However, generation of an immune response does
require that DCs and tumor cells be tightly associated before
injection, inasmuch as mock-fused cocultured cells were immunogenic,
but the same number and ratio of DCs and tumor cells injected together
without in vitro coculture were not (Table I, Fig. 2B). These results are in agreement with those of Guo
et al. (20) and Gong et al. (21), who similarly compared the
immunogenicity of APC-tumor cell fusions with coinjected APCs and tumor
cells. However, the immunogenicity of cellular vaccines consisting of
the unselected products of DC-tumor cell fusions or DCs and tumor cells
that have been cocultured but not fused was not directly evaluated
(21). It is also notable that immunizations with DCs and tumor cells
that were cocultured in chambers separated by a permeable membrane were
not immunogenic (Table I, Fig. 2). Although this suggests that
immunogenicity was not mediated by the transfer of soluble factors,
this possibility cannot be ruled out because functional transfer of Ag
or other factors may depend on localized release and uptake and may be
more efficient when cells are closely associated. In this way,
intimately associated DCs and tumor cells could communicate in an
"autocrine" fashion.
DCs can be found within tumors in vivo and in some instances DC infiltration has been associated with improved prognosis. This association may represent a "natural" correlate of the immunogenicity we observe following injection of ex vivo-associated DCs and tumor cells. Clearly, DC infiltration into tumors is not always sufficient for tumor rejection. Recent studies suggest that at least in some instances, mature DCs from tumor-bearing hosts can have defects in APC function (28). In addition, human cancer cells can release soluble factors that can inhibit the maturation of DCs (29). The immunization strategy we describe here could circumvent tumor-induced APC dysfunction by utilizing functional DCs derived from DC precursors in vitro. In this regard, recent studies suggest that DCs grown from precursors obtained from tumor-bearing hosts can be effective Ag delivery vehicles for tumor immunotherapy (30). Whether or not injection of functional, in vitro-derived DCs directly into tumors in vivo will induce a tumor-specific immune response has yet to be determined. The immunogenicity of DC-tumor cell conjugate vaccines supports the feasibility of this approach.
DC-tumor cell conjugate vaccines have several features that suggest potential translational applications for the immunotherapy of human tumors. Human DCs, phenotypically and functionally similar to the murine DCs used in our studies, can be obtained readily by in vitro culture of peripheral blood-derived precursors (18). Preparation of the DC-tumor cell immunogen is rapid and does not require additional selection of stable fusion products, minimizing the interval between tumor excision and immunization and suggesting a potentially broad application to multiple tumor types. DC-tumor cell association occurs with high efficiency, and injected cells are irradiated and nonproliferating. DC-tumor cell immunization has the potential to stimulate immunity against multiple tumor Ags and could induce synergistic protection through CD4+ and CD8+ T cell-mediated immune responses. Because the tumor cell is the source of Ag, immunizations would not depend on the prior identification of unique or "shared" tumor Ags and would not be limited to individuals expressing a particular corresponding MHC allele. Furthermore, because the immunization is patient specific, it could stimulate immunity against uniquely expressed tumor Ags that may be an important component of an effective antitumor response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Louis D. Falo, Jr., Department of Dermatology, University of Pittsburgh School of Medicine, 190 Lothrop Street, Pittsburgh, PA 15213. E-mail address:
3 Abbreviations used in this paper: DCs, dendritic cells; PEG, polyethylene glycol.
Received for publication December 12, 1997. Accepted for publication January 23, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and Discussion References |
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) or
irradiated whole cell vaccines consisting of identical numbers of tumor
cells alone (
), DCs alone (
), cells from DC-tumor fusions (
)
or mock fusions (i.e., coculture, •). Where indicated, mice were
immunized with identical numbers of cells derived from DC-tumor cell
cocultures incubated in separate chambers of Transwell plates (Fig.
A and C, 
) or with DCs and tumor cells
injected together without prior coculture (B, 