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Tumor Biology |
Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213
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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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Interactions between tumor cells and cells of the immune system appear to be critical for tumor growth and progression. Tumor-derived factors dramatically alter the function and survival of immunocompetent cells in the local tumor microenvironment as well as systemically (2 , 3) . One class of immunosuppressive molecules, which may be responsible for the rapid progression of tumor, are gangliosides (4, 5, 6, 7, 8) . Blood levels of gangliosides have been shown to positively correlate with neoplastic growth in patients with diverse tumors. Sialylated lacto-series gangliosides have also been identified as antigens in human epithelial cancers (9) . A number of tumors, including NB, melanoma, retinoblastoma, and hepatoma, are known to overexpress and shed gangliosides into the circulation. For example, analysis of serum obtained from patients with NB showed a 50–100-fold increase in the levels of GD2 ganglioside (10) . Increased levels of GD2 and GM3 were also detected in patients with retinoblastoma and hepatoma, respectively (11 , 12) . GD3 and GM3 gangliosides were identified in the sera of patients with malignant melanoma (12) and head and neck carcinoma, respectively (13) .
Evidence suggests that exogenous or tumor-derived gangliosides are able
to inhibit function of immune cells and promote tumor growth. For
instance, addition of tumor-derived gangliosides to the tumor cell
innoculum enhances tumor formation in mice (14)
.
Gangliosides, predominantly GD2, isolated from
the human NB cell line LAN5, inhibit murine cellular immune responses
in vivo (15, 16, 17)
. Purified or tumor-derived
gangliosides inhibit mitogen-stimulated proliferation of human
peripheral blood lymphocytes (18
, 19)
, as well as
IL-2-dependent growth of murine T cell lines (20)
.
Gangliosides also inhibit production of TNF-
and antigen
presentation by human monocytes (18
, 19
, 21)
, natural
killer cell cytotoxicity (22)
, and IFN-
-induced immune
responses (23)
.
Gangliosides have also been shown to contribute to tumor-induced bone marrow suppression and may alter hematopoiesis (24 , 25) . For instance, patients with NB bone marrow metastases often suffer from disturbed hematopoiesis, resulting in pancytopenia (26) . Furthermore, Sietsma et al. (27) have demonstrated that murine NB neuro-2a (N2a) cell-derived gangliosides, mainly GM3, dose dependently inhibit erythropoiesis and myelopoiesis. Gangliosides isolated from the plasma of NB patients, such as GD2, GM2, and GM3, down-regulated erythroid and myeloid colony formation from human CD34+ precursors in vitro (27) . However, the role of gangliosides in the regulation of DC generation (dendropoiesis) has not been studied. DCs, the most potent professional antigen-presenting cells, play a crucial role in the induction of specific antitumor immune responses (28) , and the inhibition of their function and/or formation represents an important mechanism by which tumors escape immune recognition (29) . Thus, the primary goal of this study was to evaluate the role of NB-derived gangliosides on DC generation and function. We have demonstrated that NB-derived gangliosides, as well as purified gangliosides added to DC cultures, inhibit the generation of functionally active DCs from both human CD34+ and murine hematopoietic precursor cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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NB Cell Lines.
Human SK-N-BE and murine Neuro-2a NB cell lines were obtained from
American Type Culture Collection and were grown in complete medium:RPMI
1640 (Life Technologies, Inc., Grand Island, NY) supplemented with 10%
heat-inactivated FCS, 1 mM sodium pyruvate, 2
mM L-glutamine, 100 units/ml penicillin, and
100 µg/ml streptomycin (Life Technologies, Inc.).
Preparation of Mouse and Human DCs.
Human DCs were generated from CD34+ precursors isolated from umbilical
cord blood using a MACS isolation kit (Miltenyi Biotec, Inc., Auburn,
CA). After positive selection, CD34+ progenitors were cultured at
10–20 x 105 cells/ml in 24-well plates in
complete medium supplemented with 1000 units/ml GM-CSF, 1000 units/ml
IL-4, 2.5 ng/ml TNF-, and 10 ng/ml SCF. Fresh cytokines were added
every 3 days except for SCF, which was added for only 1 week. Cultured
human DCs were collected 17–18 days later and used for further
analyses. Confirmation of DC phenotype was performed using DC-related
markers, including FITC- or PE-labeled antibodies recognizing CD83,
CD86, CD80, and HLA-DR molecules (PharMingen, San Diego, CA). Flow
cytometric analyses of stained cells was performed on the Becton
Dickinson FACScan and LYSIS II software package.
Murine DCs were generated as described previously (30)
.
Briefly, mouse hematopoietic progenitors were isolated from bone marrow
and cultured in complete RPMI 1640 in six-well plates
(105 cells/ml) in the presence of 1000 units/ml
GM-CSF and 1000 units/ml IL-4. Mouse DCs were harvested on day 7 and
stained with CD11c, CD86, CD80, or MHC class II FITC- or PE-conjugated
antibodies (PharMingen). Both murine and human GM-CSF and IL-4 were
gifts from Schering-Plough (Kenilworth, NJ). TNF- and SCF were
obtained from R&D Systems (Minneapolis, MN).
MLR.
Functional activity of human and mouse DCs was determined in a one-way
allogeneic MLR using T lymphocytes as responders. Cultured human or
mouse DCs, serving as stimulators, were irradiated at 3000 rads and
added to responders (1 x 105
cells/well) at different ratios. Cells were mixed in 96-well
round-bottomed plate and incubated for 96 h. Cell cultures were
pulsed with 1 µCi of [3
H]thymidine/well for
the last 16–18 h and harvested using a Skatron (Skatron, Lier,
Norway) cell harvester. Uptake of [3
H]thymidine
was determined on a beta scintillation counter (Beta-Plate, Wallac,
Finland).
Experimental Design.
Cell culture inserts with 0.4-µm pore size (Fisher Scientific,
Pittsburgh, PA) were used to separate tumor cells and DCs in 6-well or
24-well plates to study the effect of NB-derived immunosuppressive
factors on DC generation and function. Human or mouse DC progenitors
were cultured in the lower chamber. Murine Neuro-2a (N2a), human
SK-N-BE cells, or culture medium, which served as the control, was
placed in the upper chamber inserts. Human peripheral blood mononuclear
cells and murine splenocytes were used as additional controls. NB cells
were seeded into the upper chamber on days 1 or 5 for the mouse DC
cultures or on days 1 or 7 for human DC cultures. After coincubation,
DCs were harvested and analyzed by FACScan for the expression of
DC-specific markers and the percentage of positive cells. The
functional ability of DCs to stimulate proliferation of T cells was
assessed by using an MLR assay.
Inhibition of Ganglioside Synthesis.
To inhibit ganglioside synthesis, tumor cells were cultured in the
presence of 10 µM D-PDMP (Matreya, Pleasant
Gap, PA) for 72 h. Expression of GD2
on treated and nontreated NB cells was detected using primary
anti-disialoganglioside (PharMingen) and secondary FITC-conjugated
antibodies. To evaluate the effect of purified gangliosides on DCs,
GD2 and GM3 were dissolved
in ethanol and added to DC cultures at a final concentration 5
µM for GD2 and 25 µM
for GM3. Ethanol was used as a control solvent.
Apoptosis Assay.
To determine whether GD2 causes apoptosis of
human CD34+ progenitor cells, CD34+ cells were treated with 5
µM of GD2 or ethanol (0.05%
vol/vol, control solvent) for 24 and 48 h. The early apoptotic
alterations on cell membrane were measured by an Annexin V binding
assay (PharMingen), and dead cells were identified using the propidium
iodide staining of DNA (Life Technologies, Inc.).
Statistical Analysis.
For a single comparison of two groups, the Student’s t test
was used after evaluation for normality. If data distribution was not
normal, a Mann-Whitney rank sum test was performed. For all statistical
analysis, the level of significance was set at a probability of 0.05 to
be considered significant. Data are presented as the mean ± SE.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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for 17–18 days differentiated into DCs, as was
assessed by high levels of expression of CD83 (up to 85%), MHC class
II (up to 85%), CD86 (up to 95%), and CD80 (up to 70%) molecules.
Mouse bone marrow precursors stimulated in cultures with murine GM-CSF
and IL-4 were analyzed for the percentage and number of DCs on day 7.
Control DC cultures contained 61.1% CD11c+ CD86+ cells and 60.2%
CD11c+ MHC class II+ double-positive cells.
Addition of NB cells to DC cultures demonstrated that soluble
NB-derived factors inhibited DC generation in both human and mouse
models (Figs. 1
and 2)
. For instance, in the presence of N2a cells, the percentage of CD11c+
class II+ cells in mouse bone marrow-derived DC cultures decreased from
60.2 ± 3.9% in control to 24.1 ± 2.2%
in NB-treated cultures (P < 0.01). In
addition, the percentage of CD11c+ CD86+ cells decreased in these
cultures from 61.1 ± 4.9% to 29.3 ± 3.1%, respectively (P < 0.01; Fig. 2
).
Inhibition of expression of DC-specific markers was more significant
when NB cells were added to DC cultures on day 1 as compared with day
5. Addition of N2a tumor cells to mouse DC cultures on day 5 resulted
in a decrease in CD11c+ class II+ and CD11c+ CD86+ cells from
60.2 ± 5.7% to 37.1 ± 3.4%
(P < 0.05) and 61.1 ± 4.6%
to 45.3 ± 3.4% (P < 0.05),
respectively (Fig. 2)
. However, the inhibition was significantly less
than that observed in DC cultures coincubated with NB cells starting on
day 1.
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. For example, inhibition of DC production from
CD34+ precursors was also significantly greater when SK-N-BE cells were
added to hematopoietic precursors on day 1 as compared with those
obtained on day 5 (data not shown; P < 0.05). As shown in Fig. 1
, SK-N-BE-derived factors caused significant
decreases in the appearance of CD83+, CD86+, CD80+ cells in these
cultures (P < 0.01). However, expression of
MHC class II molecules was not significantly changed in the presence of
NB cells (data not shown). Interestingly, NB-derived factors caused
alterations of DC differentiation but did not change the number of
cells in cultures. Together, these results demonstrate that murine NB
cells (N2a) and human NB cells (SK-N-BE) significantly inhibited murine
and human DC generation in cultures.
Inhibition of APC Function in DC Cultures by Coincubation with NB.
To determine whether NB-derived factors affect the functional
activity of DCs to induce T-cell proliferation, we evaluated the
stimulatory capacity of cells harvested from control or NB-treated DC
cultures for their ability to induce proliferation of allogeneic T
cells in an MLR assay. As shown on Fig. 3
, coincubation of DC cultures with either SK-N-BE or N2a cells on day 1
significantly decreased their ability to induce T-cell proliferation.
In human studies, the maximum inhibition of T-cell proliferation was
observed at APC:T cell ratios 0.9:1 and 0.3:1:33,508 ± 1,613 cpm for control versus 17,428 ± 152
cpm for SK-N-BE treated cultures (P < 0.01)
and 32,714 ± 5,785 versus 15,967 ± 1,888 cpm (P < 0.01), respectively
(Fig. 3A)
. Similarly, the level of suppression of murine
T-cell proliferation induced by pretreatment of DC cultures with N2a
tumor cells reached 30% (P < 0.01; Fig. 3B
). It is important to note that when the coincubation of
DC cultures with NB cells was initiated at day 5 or later, a decrease
in DC numbers and their capacity to stimulate allogeneic T cells was
also detected but to a significantly lesser extent in both murine and
human systems (data not shown). This suggests that NB-derived factor(s)
affect the development of early hemopoietic progenitors. These results
confirm that human and murine NB produce factors that inhibit the
generation of DCs in vitro, as assessed by a significant
decrease in the APC activity of cultured cells. The level of inhibition
was time dependent, with the most profound inhibition observed when
tumor cells were added at an early time to the culture of hemopoietic
progenitors.
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To test this hypothesis, we examined whether purified
GD2 (5 µM) or
GM3 (25 µM) affect differentiation
of human CD34+ or mouse bone marrow progenitors into mature DCs. The
doses of gangliosides were chosen according to earlier published data
(27)
. GD2 and
GM3 were added to DC cultures on day 1 and then
every third day. The number of DCs differentiated from CD34+ precursors
in the GD2-treated groups was 3-fold less when
compared with DC number in control culture. As we have mentioned above,
SK-N-BE cells express GD2 and altered DC
generation but not the number of DCs in cultures. The absence of the
effect of SK-N-BE cells on DC proliferation is likely attributable to
the influence of other SK-N-BE-derived factors. Expression of CD83
molecules on cultured cells decreased from 51.8 ± 6.1%
in control groups to 12.9 ± 2.7% in cultures treated
with GD2 (P < 0.05).
Similarly, the percentage of CD86+ cells in the same cultures decreased
from 32.4 ± 2.5% to 7.4 ± 1.8% after
addition of GD2 (P < 0.01; Fig. 4
). The percentages of double-positive CD83+ CD80+ and CD83+ HLA-DR+
cells were three times less in GD2-treated
cultures in comparison with nontreated cultures (P < 0.05). Because we have observed that GD2
decreases the number of DCs differentiated from CD34+ progenitors, we
hypothesized that this effect might be mediated by the induction of
apoptosis. To check this possibility, CD34+ precursor cells were
treated with GD2 (5 µM)
or control solvent (0.05% ethanol) for 24 and 48 h, collected and
analyzed by Annexin V-FITC binding. The levels of Annexin V-positive,
propidium iodide-negative cells in the treated and untreated cultures
were 15.9 ± 3.1% and 10.9 ± 2.7%,
respectively (P > 0.05). These data suggest
that GD2-induced inhibition of dendropoiesis was
not mediated by apoptotic death of early hematopoietic progenitors.
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. Furthermore, APC function of DC cultures treated with
GM3 was also inhibited. The level of suppression
of murine T-cell proliferation induced by pretreatment of DC cultures
with GM3 reached 38% (P < 0.05) at an APC:T cell ratio of 1:1 (Fig. 5B)
. Taken
together, these results demonstrate that purified gangliosides
GD2 and GM3 inhibit the
generation of human and murine DCs in vitro.
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, which is in agreement with others (16
, 27)
.
D-PDMP-treated and nontreated cells were added to DC
cultures. Control DC cultures and DC cultures generated in the presence
of D-PDMP-treated (PDMP+) or nontreated (PDMP-) NB cells
were evaluated for their capacity to induce proliferation of allogeneic
T cells in an MLR assay. Fig. 7
represents the results of these experiments. Cultured APCs generated in
the presence of PDMP-/SK-N-BE cells had a significantly decreased
ability to induce T-cell proliferation compared with APCs generated
with PDMP+/SK-N-BE (P < 0.05; Fig. 7
),
suggesting that block of ganglioside synthesis in NB cells decreases
their ability to inhibit generation of functionally active DCs. For
instance, at an APC:T cell ratio of 0.3:1, APCs exposed to
PDMP-/SK-N-BE cells had only 41 ± 4% of stimulatory
activity of control APCs, whereas APCs exposed to PDMP-treated SK-N-BE
cells demonstrated 69 ± 5% of control activity
(P < 0.05). These data demonstrate that PDMP
treatment decreases NB-mediated inhibition of APC activity up to 65%.
The partial recovery of APC function after PDMP treatment of NB cells
is in a good correlation with a partial inhibition of ganglioside
levels observed in PDMP-treated tumor cells. The similar results were
observed when murine NB cells were treated with
D-PDMP. For example, N2a treatment of murine DC
cultures caused inhibition of T-cell proliferation (1:1 APC:T cell
ratio) from 48,320 ± 3,751 cpm for control APCs to
11,406 ± 983 cpm for APCs obtained from N2a-treated
cultures (P < 0.05). Inhibition of
ganglioside synthesis with PDMP treatment resulted in the partial (up
to 23%) reversal of NB-induced inhibition of DC stimulatory activity.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A common feature in patients with NB and bone marrow metastases is the occurrence of disturbed hematopoiesis. (28 , 32) . One possible group of molecules potentially responsible for NB-induced bone marrow suppression are gangliosides (32) . It has been reported recently that both gangliosides shed by NB cells and exogenous gangliosides inhibited myelopoiesis and erythropoiesis in vitro (28) . Here we demonstrated that gangliosides inhibit human and mouse DC generation. The major ganglioside expressed by human SK-N-BE cells and murine N2a cells is GD2 and GM3, respectively. To determine whether inhibitory effects of NB-derived factors on dendropoiesis is mediated by gangliosides, the biosynthesis of gangliosides in tumor cells was inhibited by D-PDMP (16 , 17) . D-PDMP treatment of SK-N-BE cells for 72 h caused inhibition of GD2 expression up to 50% as compared with D-PDMP-untreated NB cells. Blockage of ganglioside synthesis partly reversed the NB-induced inhibition of DC generation. Moreover, purified GD2 and CM3 suppressed differentiation of CD34+ cells and bone marrow precursor cells into functionally active DCs, respectively. Thus, purified gangliosides and NB-derived gangliosides are potent inhibitors of DC generation.
Gangliosides are also associated with inhibition of the activity of
several other immune cells including helper T cells (33
, 34) , natural killer cells (35)
, and antigen- and
mitogen-stimulated T and B cells (36, 37, 38)
. Ladisch
et al.
(19)
first demonstrated that gangliosides may inhibit the accessory function of monocytes in 1984. Brain-derived gangliosides regulate the cytokine production and proliferation of activated T cells. Gangliosides suppress TNF- production in human monocytes by acting on early stages of activation (>21
).
They block antigen presentation by human monocytes (39)
and cause down-regulation of constitutive and IFN--inducible
expression of MHC class I and II molecules on astrocytes
(40)
. The inhibitory effects of tumor-derived gangliosides
on cells of the immune system have also been well demonstrated in
vivo. For instance, gangliosides, isolated from the plasma of
cancer patients are highly immunosuppressive and regulate a variety of
immune functions in vivo (15
, 16
, 41
, 42)
.
Immunosuppression caused by gangliosides may be mediated by several mechanisms. These include direct binding to cytokines such as IL-2, preventing its interaction with IL-2 receptor (20 , 23 , 43) . By a similar mechanism, the preincubation of CSFs with bovine brain mixed gangliosides resulted in decreased numbers of colonies of bone marrow-derived granulocyte/macrophage progenitor cells (44) . Direct binding of gangliosides to CSFs may also be one of the means by which NB cells inhibit dendropoiesis. In fact, competitive binding of gangliosides with growth factors may explain why transduction of C1300 murine NB cells with genes encoding IL-2 or GM-CSF results in abrogation of their tumorigenicity and decreased growth of liver metastasis (45) .
In addition, gangliosides may physiologically function to coordinate
the activation of multiple receptors. They modify the binding activity
of individual receptors as well as receptor-specific signal
transduction pathways (46)
. For instance, programmed cell
death might be mediated in part by ganglioside derivatives because
ceramide is a constitutive component of their structure and may be
released during the interaction of tumor and immune cells. Recently, it
has been demonstrated that mouse bone marrow cells treated in
vitro with gangliosides, derived from T-cell lymphoma, undergo
apoptotic cell death. The major ganglioside produced by this tumor is
GD3. In fact, the anti-GD3
antibody protected bone marrow cells from tumor-induced apoptosis
(47)
. However, we have shown here that
GD2-induced inhibition of dendropoiesis in
cultures is not mediated by apoptosis of hematopoietic precursors. It
is known that the ceramide portion of gangliosides contains a fatty
acid chain. The length of this chain determines the killing ability of
gangliosides (48)
. Thus, GD2 does
not cause the apoptosis of hematopoietic precursor cells but probably
has an effect on DC generation by changing the binding of growth
factors with their receptors. Ceramide itself, as an important
constituent of gangliosides, blocks phosphorylation of the
retinoblastoma gene product, which is an important regulator of cell
cycle. Inhibition of phosphorylation of retinoblastoma results in cell
cycle arrest (49)
. In contrary, purified ceramide, but not
ganglioside, has been shown to induce apoptosis in a model system
(50)
. Gangliosides have also been shown to block the
activation of nuclear factor-
B in T cells, a transcriptional factor
involved in the expression of several cytokine genes (23
, 51)
. We have also observed NB-induced inhibition of NF-B
expression in cultured
DCs.4
This suggests that NB-derived gangliosides may not only inhibit binding
of growth factors with receptors on the surface of hemopoietic
precursors but also have a direct effect on their survival. We have
demonstrated recently that tumor-derived factors cause inhibition of DC
survival and stimulate their apoptotic death (52
, 53)
.
However, it is unclear whether gangliosides may induce apoptosis in
hemopoietic progenitors. Further studies are necessary to clarify this
mechanism.
Tumor-associated gangliosides can also be considered as antigens specific for several types of tumor including NB, melanoma, and lung cancer. Gangliosides thus could be used as a target in different immunotherapeutic approaches (31 , 54 , 55) . Further understanding and elucidating of the mechanisms of immunosuppression induced by gangliosides may lead to the discovery of a new therapeutic agent that will be directed to decrease tumorigenicity and increase immunogenicity of NB cells.
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FOOTNOTES |
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1 This study was supported by the Robert Wood
Johnson Foundation, the Minority Medical Faculty Program, Grant
RWJ29219 (to E. M. B.), Children’s Hospital of Pittsburgh Start up
Funds (to E. M. B.), NCCF Grant 2UF10CA, and Grant RO1 CA80126 (to
M. R. S.). 
2 To whom requests for reprints should be
addressed, at Children’s Hospital of Pittsburgh, Department of
Pediatric Surgery, 3705 Fifth Avenue, Floor 4A, Room 485, Pittsburgh,
PA 15213. Phone: (412) 692-8735; Fax: (412) 692-6069; E-mail: barksde{at}chplink.chp.edu
3 The abbreviations used are: NB, neuroblastoma;
DC, dendritic cell; IL, interleukin; TNF, tumor necrosis factor;
GM-CSF, granulocyte/macrophage-colony stimulating factor; SCF, stem
cell factor; PE, phycoerythrin; MLR, mixed leukocyte reaction; APC,
antigen-presenting cell; FACS, fluorescence-activated cell sorter;
D-PDMP,
DL-threo-1-phenyl-2-decanolylamine-3-morpholino-1-propanol
HCl.
Received 12/23/99. Accepted 10/23/00.
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N. Abboushi, A. El-Hed, W. El-Assaad, L. Kozhaya, M. E. El-Sabban, A. Bazarbachi, R. Badreddine, A. Bielawska, J. Usta, and G. S. Dbaibo Ceramide Inhibits IL-2 Production by Preventing Protein Kinase C-Dependent NF-{kappa}B Activation: Possible Role in Protein Kinase C{theta} Regulation J. Immunol., September 1, 2004; 173(5): 3193 - 3200. [Abstract] [Full Text] [PDF]
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T. L. Whiteside, J. Stanson, M. R. Shurin, and S. Ferrone Antigen-Processing Machinery in Human Dendritic Cells: Up-Regulation by Maturation and Down-Regulation by Tumor Cells J. Immunol., August 1, 2004; 173(3): 1526 - 1534. [Abstract] [Full Text] [PDF]
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 L. M. Wagner, C. A. Billups, W. L. Furman, B. N. Rao, and V. M. Santana Combined Use of Erythropoietin and Granulocyte Colony-Stimulating Factor Does Not Decrease Blood Transfusion Requirements During Induction Therapy for High-Risk Neuroblastoma: A Randomized Controlled Trial J. Clin. Oncol., May 15, 2004; 22(10): 1886 - 1893. [Abstract] [Full Text] [PDF]
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M. V. Thornton, D. Kudo, P. Rayman, C. Horton, L. Molto, M. K. Cathcart, C. Ng, E. Paszkiewicz-Kozik, R. Bukowski, I. Derweesh, et al. Degradation of NF-{kappa}B in T Cells by Gangliosides Expressed on Renal Cell Carcinomas J. Immunol., March 15, 2004; 172(6): 3480 - 3490. [Abstract] [Full Text] [PDF]
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Y. Nefedova, M. Huang, S. Kusmartsev, R. Bhattacharya, P. Cheng, R. Salup, R. Jove, and D. Gabrilovich Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer J. Immunol., January 1, 2004; 172(1): 464 - 474. [Abstract] [Full Text] [PDF]
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S. Kusmartsev and D. I. Gabrilovich Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species J. Leukoc. Biol., August 1, 2003; 74(2): 186 - 196. [Abstract] [Full Text] [PDF]
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J. Peguet-Navarro, M. Sportouch, I. Popa, O. Berthier, D. Schmitt, and J. Portoukalian Gangliosides from Human Melanoma Tumors Impair Dendritic Cell Differentiation from Monocytes and Induce Their Apoptosis J. Immunol., April 1, 2003; 170(7): 3488 - 3494. [Abstract] [Full Text] [PDF]
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D. I. Gabrilovich, P. Cheng, Y. Fan, B. Yu, E. Nikitina, A. Sirotkin, M. Shurin, T. Oyama, Y. Adachi, S. Nadaf, et al. H1{degrees} histone and differentiation of dendritic cells. A molecular target for tumor-derived factors J. Leukoc. Biol., August 1, 2002; 72(2): 285 - 296. [Abstract] [Full Text] [PDF]
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 V. Sriram, S. Cho, P. Li, P. W. O'Donnell, C. Dunn, K. Hayakawa, J. S. Blum, and R. R. Brutkiewicz Inhibition of glycolipid shedding rescues recognition of a CD1+ T cell lymphoma by natural killer T (NKT) cells PNAS, June 11, 2002; 99(12): 8197 - 8202. [Abstract] [Full Text] [PDF]
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T. K. Hoffmann, J. Muller-Berghaus, R. L. Ferris, J. T. Johnson, W. J. Storkus, and T. L. Whiteside Alterations in the Frequency of Dendritic Cell Subsets in the Peripheral Circulation of Patients with Squamous Cell Carcinomas of the Head and Neck Clin. Cancer Res., June 1, 2002; 8(6): 1787 - 1793. [Abstract] [Full Text] [PDF]
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C. C. Sombroek, A. G. M. Stam, A. J. Masterson, S. M. Lougheed, M. J. A. G. Schakel, C. J. L. M. Meijer, H. M. Pinedo, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4333 - 4343. [Abstract] [Full Text] [PDF]
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) to stimulate
proliferation of allogeneic T cells was assessed in a MLR assay.
Cultures were maintained for 96 h, and [3H]thymidine
was added 18 h before the harvesting. Results are expressed as
mean cpm from triplicate cultures; bars, SE. These
results are representative of three independent experiments.
) to stimulate allogeneic T-cell
proliferation compared with untreated control DCs (
) was determined
in a MLR assay. MLR cultures were maintained for 96 h, and
[3H]thymidine was added 18 h before the harvesting.
Results are expressed as the mean cpm of triplicate cultures;
bars, SE. These results are representative of three
different experiments.
)
or nontreated with D-PDMP (