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Baylor Institute for Immunology Research, Dallas, TX 75204
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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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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Complete culture medium (CM) consisted of RPMI 1640, 1% L-glutamine, 1% penicillin/streptomycin, 50 µM 2-ME, 1% sodium pyruvate, 1% essential amino acids, and heat-inactivated 10% FCS (Life Technologies, Grand Island, NY). The recombinant human cytokines used were IL-2 (Genzyme, Cambridge, MA), GM-CSF (GM-CSF Leukine, Immunex, Seattle, WA), trimeric CD40 ligand (Immunex), and IL-7 and IL-4 (R&D Systems, Minneapolis, MN). Cytochalasin D, cycloheximide, and DNA dye 7-aminoactinomycin D (7-AAD) were obtained from Sigma (St. Louis, MO). The tumor cell lines used were Jurkat T cell lymphoma (clone E6-1); prostate carcinomas DU145, PC3, and LNCap; and malignant melanomas A375.S2, A2058, and Colo829; all were purchased from American Type Culture Collection (Manassas, VA) and maintained in CM.
Cell purification
Purified B cells and CD4+ and CD8+ T cells were obtained from Ficoll-separated PBMC of healthy volunteers (with no history of blood transfusion) depleted of other cells using purified CD3 (UCHT1), CD4 (13B8.2), CD8 (B9.11), CD14 (RMO52), CD16 (3G8), CD19 (J4.119), CD56 (NKH-1), anti-HLA-DR (B8.12.2), and anti-glycophorin A (D2.10) mAbs (Beckman-Coulter, Miami, FL) and goat anti-mouse IgG Dynabeads (Dynal, Lake Success, NY). The purity of the enriched populations was >85%.
Generation of DC
Immature monocyte-derived DC were generated from the adherent fraction of peripheral blood PBMC (20). Briefly, PBMC were suspended in CM and allowed to adhere to plastic dishes (Falcon six-well plates, Becton Dickinson, Franklin Lakes, NJ). After 2-h incubation at 37°C, the nonadherent cells were removed, and the adherent cells were cultured in CM with GM-CSF (100 ng/ml) and IL-4 (5 ng/ml). Cultures were fed every 2 days. Cells were routinely used on day 6, and DC recovery, as determined by immunofluorescence and flow cytometry, was >90% of CD1a+ CD14- cells.
Induction of tumor cell death
Cell death was induced by 16-h treatment with anti-Fas mAb
(1 µg/1.0 x 106/ml; clone CH-11,
Beckman-Coulter). The PC3 prostate cancer cell line required prior
sensitization with cycloheximide (25 µg/ml) for 2 h followed by
anti-Fas treatment. LNCap cell death was induced by gamma
irradiation (80 Gy) 24 h after exposure to TNF-
(40 ng/ml).
Alternatively, tumor cells were induced to die by gamma irradiation
(100 Gy) followed by overnight culture in CM. Cell death was assessed
by morphology, externalization of phosphatidylserine using FITC-labeled
annexin V, and staining with the DNA-specific dyes, 7-aminoactinomycin
D (7-AAD) and trypan blue.
Phagocytosis of apoptotic tumor cells
Killed tumor cells were washed with PBS and labeled with 7-AAD at a concentration of 20 µg/ml/106 cells for 30 min at 4°C. The labeled tumor cells were subsequently cocultured with CD1a-labeled immature DC at a 1/5 ratio (selected from preliminary experiments) at 4°C or 37°C. After 1 h cells were washed and treated with 0.05% trypsin/0.02% EDTA for 5 min to disrupt cell-cell binding. Phagocytosis was quantified by flow cytometry as the percentage of double-positive cells (CD1a+ 7-AAD+).
For confocal microscopy, cells were allowed to adhere on poly-L-lysine-coated slides (Baxter Diagnostic, Deerfield, IL) for 30 min at room temperature, fixed with 4% paraformaldehyde/PBS for 15 min, washed with PBS, and mounted. Confocal microscopy was performed using a Leica TCS-NT SP (Deerfield, IL) equipped with Ar, Kr, and He-Ne lasers and a spectrophotometer to separate the detection channels of FITC (510–550 nm) and 7-AAD (600–660 nm). Simultaneous acquisition of FITC and 7-AAD and transmission set for differential interference contrast (DIC) were performed using the 488- and 568-nm laser lines reflected with a 488/568 double dichroic mirror. Images were generated using the PL-APO x100 objective, zoomed x2, and measured in the 1024 x 1024 format.
Blocking of phagocytosis
Immature DC were incubated with cytocalasin D (20 µm) or CD36
(thrombospondin receptor, clone CB38, PharMingen, San Diego, CA; 5
µg/ml), CD51/CD61 (vitronectin receptor
vß3, clone 23C6,
PharMingen; 5 µg/ml), annexin V (clone RUU-WAC2A, Caltag, Burlingame,
CA; 5 µg/ml), and isotype-matched controls mAbs for 30 min. DC were
washed and used in the phagocytosis assay as described above.
T cell proliferation assay
CD1a-labeled DC were cocultured with unlabeled tumor cell bodies, sorted based on CD1a expression (purity, >98%), and cultured at graded doses in CM with 10% human AB serum, autologous PBMC (1 x 105 PBMC/well/200 µl), purified CD4+ T cells, or purified CD8+ T (5 x 104/well/200 µl) cells. In cultures with CD8+ T cells, soluble CD40 ligand (CD40L; 200 ng/ml) and IL-2 (5 U/ml) were added to induce DC maturation and to support T cell proliferation. Proliferation was determined after 5 days by uptake of tritiated thymidine (1 µCi/well for the last 16 h).
mAb blocking assays
For blocking experiments, DC were incubated with mAbs against HLA-DR (clone L243, Becton Dickinson; 5 µg/ml) and HLA-A,B,C (W 6/32, Dako, Carpenteria, CA; 5 µg/ml) for 30 min before the addition of T cells, and the mAbs were left throughout the culture period. Irrelevant mAbs were used as isotype controls.
Generation of CTL
DC were loaded with killed tumor cells, sorted, and cultured with autologous PBMC or purified CD8+ T cells at 0.5–1 x 105 DC/ml and 2 x 106 T cells/ml in a final volume of 2 ml. IL-7 (10 U/ml) was added in the first cycle. T cells were restimulated every week with tumor-loaded DC, and IL-2 (10 U/ml) was added in the second and third cycles. T cells were harvested after 3 wk, and CTL activity was tested in a standard chromium release assay using sensitized tumor cells, unloaded and peptide-loaded T2 cells, and K562 cells as targets.
Synthetic peptides and peptide binding to HLA-A2
The synthetic PSA peptides used were PSA1 (NH2-FLTPKKLQCV; aa 141–150) and PSA2 (NH2-KLQCVDLHV; aa 146–154; Biosynthesis, Lewisville, TX). HLA-A2 binding affinity of the PSA peptides was evaluated by up-regulation of HLA-A2 surface expression on T2 cells after overnight peptide loading in serum-free CM (50 µg peptide/ml/1 x 106 T2 cells). The T2 cells were washed and stained with FITC-conjugated HLA-A2-specific mAb (28, HLA-A2, One Lamda, Canoga Park, CA). The mean fluorescence intensity of HLA-A2 staining was analyzed by flow cytometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first determined the capacity of immature monocyte-derived DC
to capture killed tumor cells (>80% of dead cells as determined by
annexin V binding and propidium iodide staining). The capture of
representative DNA-labeled (7-AAD) killed tumor cells (DU145) by
CD1a-labeled DC was determined by flow cytometry as the percentage of
FITC-CD1a+ DC that expressed the red dye 7-AAD
(Fig. 1
A). Forward
scatter/side scatter analysis revealed the increased granularity of the
double-positive population, further confirming the capture of tumor
cell bodies by DC (Fig. 1A). As shown in Fig. 1B,
up to 45% of DC are able to capture cell bodies derived from various
tumor cell lines, including the melanoma cell lines (A2058, A375.S2),
prostate carcinoma cell lines (DU145, PC3, LNCap), and Jurkat T
lymphoma. The extent of phagocytosis was independent of whether cell
death was induced by Fas ligation or gamma irradiation (data not
shown). The phagocytosis was also seen in an autologous setting where
bodies of EBV-transformed B lymphoblastoid cells or nontransformed B
cells were used (data not shown). Confocal microscopy examination of
cells revealed that DC indeed internalize the killed tumor cells (Fig. 2). The fate of internalized cell bodies
within DC was analyzed after coculture and subsequent staining with
FITC-labeled HLA-DR Ab. After 1 h of coculture DNA labeled cell
bodies (red) were detected inside the DC in compartments distinct from
MHC class II compartments (green, Fig. 2b). However, after
4 h the two compartments were merged (Fig. 2c).
Together, these results demonstrate that immature DC have the ability
to phagocytose cell bodies derived from different tumor cell lines.
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Previous studies demonstrated that thrombospondin receptor CD36
and vitronectin receptor
(vß3, CD51/CD61)
mediate the engulfment of cell bodies from HeLa cells or
influenza-virus infected monocytes by immature DC (21, 22). Our results confirm that phagocytosis of killed tumor cells
is an active process that is temperature dependent and requires intact
cytoskeleton, as immature DC failed to capture Jurkat cell bodies when
incubated at 4 or 37°C in the presence of cytocalasin D (Fig. 3A). As shown in Fig. 3A, both anti-CD36 and
anti-vß3 Abs were
able to partially inhibit, either alone or in combination, the
engulfment of tumor bodies by immature DC. However, neither annexin V
nor isotype-matched control mAbs blocked the uptake of tumor bodies by
DC (Fig. 3A). Finally, while immature DC homogeneously
express CD36, only a fraction expressed vitronectin receptor (Fig. 3B), suggesting a heterogeneity of DC with regard to the
receptors used for capture of tumor bodies.
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We next determined whether DC that captured killed allogeneic
tumor cells can present tumor cell-derived Ags, whether alloantigens or
tumor-specific Ags, as shown by induction of autologous T cells
proliferation. To this end, DC were loaded with tumor cell bodies,
sorted, and used as stimulators for autologous T cells, including
unseparated PBMC, purified (>90%) CD4+ T cells,
and purified (>90%) CD8+ T cells. As shown in
Fig. 4A, immature DC loaded
with Jurkat lymphoma bodies induced the proliferation of autologous
CD4+ T cells. Furthermore, DC loaded with DU145
prostate carcinoma cell bodies induced the proliferation of autologous
CD8+ T cells (Fig. 4B). Initial
experiments indicated that the induction of DC maturation by exogenous
CD40L and the addition of IL-2 were necessary to induce maximal
proliferation of purified CD8+ T cells (data not
shown). In addition, induced T cell proliferation was not due to
autoreactivity, because DC loaded with killed nontransformed B cells
autologous to DC and T cells resulted in no T cell proliferation
(comparable counts per minute of <600 at 5000 DC/well to background
were obtained). In blocking experiments CD4+ and
CD8+ T cell proliferation induced by immature DC
loaded with killed malignant melanoma, Colo 829, or prostate carcinoma,
LNCap, cells was strongly inhibited by the presence of mAbs against MHC
class II and class I molecules, respectively (Fig. 4, C and
D). Although macrophages were more potent in capturing
EBV-transformed cell bodies than immature DC, they failed to elicit
CD8+ T cell responses (data not shown). These
results demonstrate that loading of immature DC with various killed
tumor cells initiates both MHC class I- and class II-restricted T cells
proliferation.
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To establish whether the loading of DC with tumor cell bodies
allows expansion of CTL with cytotoxic activity against the immunizing
tumor cell line, CD8+ T cells were cocultured
with autologous DC loaded with DU145 prostate carcinoma cell bodies
(two cycles of 7 days). The cytotoxic activity of expanded
CD8+ T cells was determined using either the
DU145 prostate carcinoma cell line or NK-sensitive K562 cells as
targets. As shown in Fig. 5A,
the expanded T cells could kill the prostate carcinoma cells used for
immunization, but not the K562 target, thereby demonstrating CTL rather
than NK activity. CTL with equivalent cytotoxic activity were also
expanded against the immunizing tumor cell line when total PBMC, rather
than purified CD8+ T cells, were used as
responder cells (Fig. 5A).
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B), and the expanded CTL were able to kill the PC3 cells
used for sensitization as well as another prostate carcinoma cell line,
DU145. In addition, the CTL activity elicited by DC loaded with DU145
prostate carcinoma cell bodies was able to kill PC3 cells (up to 23%
specific lysis at a 30:1 E:T cell ratio). This suggests that DC loaded
with killed tumor cells elicit CTL with cytotoxic activity against
other tumor cells expressing shared Ags, whether alloantigens or
tumor-specific Ags. DC loaded with bodies of the prostate carcinoma LNCap cell line induce PSA-specific CTL
The next fundamental question was whether the allogeneic tumor
cell-loaded DC can elicit tumor Ag-specific CTL. To address this
question we used the allogeneic prostate carcinoma cell line LNCap that
expresses a known tumor-specific Ag PSA (23, 24). As shown
in Fig. 6, immunofluorescence staining
confirmed the cytoplasmic expression of PSA in LNCap cells (Fig. 6, b and d), but not in PSA-negative control cells
(Fig. 6, a and c). Immature DC generated from
HLA-A201 donors were cocultured with LNCap cell bodies, sorted, and
used as stimulators of autologous CD8+ T cells.
After three cycles of stimulation, the responder cells were harvested,
and their cytotoxic activity and specificity were determined using
LNCap cells, K562 cells, and PSA peptide-pulsed T2 cells as targets.
The binding of PSA peptides to T2 cells was confirmed by flow cytometry
(data not shown). As shown in Fig. 7, the
elicited CTL (three cycles of stimulation) were able to lyse LNCap
cells, but not NK-sensitive K562 target cells. More importantly, the
CTL generated were able to kill PSA-pulsed T2 cells, with up to 50% of
specific lysis (5-fold increase), but neither T2 cells nor T2 cells
loaded with control influenza matrix peptide showing TAA specificity.
In addition, the elicited CTL showed increased killing of the PSA
peptide-pulsed HLA-A201+ allogeneic melanoma cell
line and autologous mature DC compared with unpulsed controls (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The loaded DC can also induce MHC class II-restricted CD4+ T cell proliferation. This is of particular importance, because CD4+ T cells can exert helper function for the induction and maintenance of tumor-specific CTL and have direct effector function against MHC class II-positive tumors as well as an indirect one by activation of other cells, e.g., macrophages. Thus, the use of allogeneic tumor cell lines may, in fact, provide help for the induction of tumor-specific immunity through CD4+ T cell responses, as mice immunized with allogeneic tumor cells expressing viral or tumor Ags develop protective immune responses (25, 26). In particular, mice immunized with B16 melanoma cells engineered to express allo-Ag were 60% tumor free upon tumor challenge compared with only 20% tumor-free mice immunized with wild-type B16 melanoma cells (26).
Our study indicates that only a fraction (up to 45%) of immature DC capture killed tumor cells. This partial capture does not seem to be due to a lack of substrate, as many labeled killed tumor cells remain unengulfed by DC. In addition, our studies confirm previous reports (21, 22) showing that engulfment of dead cells by DC is partially mediated by the thrombospondin receptor CD36 and the vitronectin receptors. Thus, the heterogeneity in DC surface receptor expression allowing for recognition/capture of killed tumor cells could be one of the factors. As both apoptosis and necrosis can occur during in vitro killing of tumor cell lines, future experiments will be performed to establish which bodies efficiently contribute to DC loading.
Major problems in tumor immunotherapy are 1) the limited number of well-defined TAA, and 2) the lack of evidence that the known TAA actually represent rejection Ags in vivo. Furthermore, the use of MHC class I binding peptides is associated with 1) the HLA restriction and 2) the limitation of induced immune responses to CD8+ T cells. In this context, the use of unfractionated antigenic material, in the form of killed allogeneic tumor cells, that provides both MHC class I and class II epitopes leading to a diversified immune response represents an attractive alternative. The possibility of using allogeneic tumor cells for targeting of TAA to DC to induce generation of TAA-specific CTL has considerable implications. First, we will be able to use allogeneic killed cells to load DC to induce both CD8+ and CD4+ T cell-mediated anti-tumor responses in patients. Furthermore, it may permit diversification of responses and recruitment of non-Ag-specific effectors, such as eosinophils, macrophages, and NK cells. These well-characterized Ag sources can permit a more rigorous clinical assessment than the ill-defined autologous tumor preparations that cannot permit standardization and are often limited in their quantity and purity. An important consequence of our novel results is that the tumor Ags do not need to be overexpressed as with transfected cells or transgenic animals. Finally, this strategy offers the possibility to identify novel shared tumor Ags that may escape detection using autologous tumors due to immunodominance of specific mutated tumor Ags unavailable from the analysis of T cell clones reacting with autologous tumors.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Karolina Palucka, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX 75204.
3 Abbreviations used in this paper: DC, dendritic cells; TAA, tumor-associated Ags; CM, complete culture medium; 7-AAD, 7-aminoactinomycin D; PSA, prostate-specific Ag; DIC, differential interference contrast; CD40L, CD40 ligand.
Received for publication February 8, 2000. Accepted for publication July 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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vß5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188:1359.vß3 integrin and requires intracellular and extracellular calcium. Eur. J. Immunol. 27:1893.[Medline]
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I. H. Frazer, R. D. Kluyver, G. R. Leggatt, H. Yang Guo, L. Dunn, O. White, C. Harris, A. Liem, and P. Lambert Tolerance or Immunity to a Tumor Antigen Expressed in Somatic Cells Can Be Determined by Systemic Proinflammatory Signals at the Time of First Antigen Exposure J. Immunol., December 1, 2001; 167(11): 6180 - 6187. [Abstract] [Full Text] [PDF]
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G. Pietra, R. Mortarini, G. Parmiani, and A. Anichini Phases of Apoptosis of Melanoma Cells, but not of Normal Melanocytes, Differently Affect Maturation of Myeloid Dendritic Cells Cancer Res., November 1, 2001; 61(22): 8218 - 8226. [Abstract] [Full Text] [PDF]
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R. Lapointe, R. E. Royal, M. E. Reeves, I. Altomare, P. F. Robbins, and P. Hwu Retrovirally Transduced Human Dendritic Cells Can Generate T Cells Recognizing Multiple MHC Class I and Class II Epitopes from the Melanoma Antigen Glycoprotein 100 J. Immunol., October 15, 2001; 167(8): 4758 - 4764. [Abstract] [Full Text] [PDF]
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C. Meyer zum Buschenfelde, J. Metzger, C. Hermann, N. Nicklisch, C. Peschel, and H. Bernhard The Generation of Both T Killer and Th Cell Clones Specific for the Tumor-Associated Antigen HER2 Using Retrovirally Transduced Dendritic Cells J. Immunol., August 1, 2001; 167(3): 1712 - 1719. [Abstract] [Full Text] [PDF]
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