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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4778-4791
Inhibition of the Differentiation of Dendritic Cells From
CD34+ Progenitors by Tumor Cells: Role of
Interleukin-6 and Macrophage Colony-Stimulating Factor
By
C. Menetrier-Caux,
G. Montmain,
M.C. Dieu,
C. Bain,
M.C. Favrot,
C. Caux, and
J.Y. Blay
From Unité Cytokine et Cancer, Unité INSERM 453, Centre
Léon Bérard, Lyon, France; and Schering Plough, Dardilly,
France.
 |
ABSTRACT |
The escape of malignant cells from the immune response against the
tumor may result from a defective differentiation or function of
professional antigen-presenting cells (APC), ie, dendritic cells (DC).
To test this hypothesis, the effect of human renal cell carcinoma cell
lines (RCC) on the development of DC from CD34+
progenitors was investigated in vitro. RCC cell lines were found to
release soluble factors that inhibit the differentiation of CD34+ cells into DC and trigger their commitment towards
monocytic cells
(CD14+CD64+CD1a CD86CD80HLA-DRlow)
with a potent phagocytic capacity but lacking APC function. RCC CM were
found to act on the two distinct subpopulations emerging in the culture
at day 6 ([CD14+CD1a] and
[CD14CD1a+]) by inhibiting the
differentiation into DC of [CD14+CD1a]
precursors and blocking the acquisition of APC function of the [CD14CD1a+] derived DC. Interleukin-6
(IL-6) and macrophage colony-stimulating factor (M-CSF) were found to
be responsible for this phenomenon: antibodies against IL-6 and M-CSF
abrogated the inhibitory effects of RCC CM; and recombinant IL-6
and/or M-CSF inhibited the differentiation of DC similarly to
RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by
an induction of M-CSF receptor (M-CSFR; CD115) and a loss of
granulocyte-macrophage colony-stimulating factor receptor 
(GM-CSFR; CD116) expression at the surface of CD34+
cells, two phenomenon reversed by anti-IL-6/IL-6R and anti-M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the
results suggest that the inhibition of DC development could represent a
frequent mechanism by which tumor cells will escape immune recognition.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
ALTHOUGH IMMUNOTHERAPY with interleukin-2
(IL-2) and/or interferon (IFN) has an established
antitumor effect in metastatic renal cell carcinoma (RCC), still a
majority of these patients will experience progressive disease after
IL-2 treatment.1,2 Tumor-specific antigens have been
reported in RCC, but tumor-specific cytotoxic T-cell clones have only
been rarely identified,3-5 suggesting a potential
impairement of the differentiation of cytotoxic T lymphocytes
(CTL) in patients with RCC. The presentation of specific
antigen peptides by major histocompatibility complex (MHC)
molecules is the initial step for the development of a specific cytotoxic T-cell response. However, tumor cells often express low or
undetectable levels of MHC class I and II antigens and most often lack
expression of costimulatory molecules (CD80 and CD86), a phenomenon
that may result in T-cell anergy.6 Dendritic cells (DC) are
professional antigen-presenting cells (APC) required for the initiation
of primary T-cell response in vivo.7,8 DC are capable of
presenting tumor-specific antigens and of activating a specific
antitumor T-cell response in vivo in animal models.8-11 DC
are likely to be involved in the development of the spontaneous or
therapeutic immune response against RCC tumor in humans, although their
precise role in tumor biology in vivo is poorly defined. In
vitro, RCC cell lines produce a wide range of cytokines, including transforming growth factor  (TGF), IL-6, basic
fibroblast growth factor (FGFb), and
granulocyte-macrophage colony-stimulating factor (GM-CSF).12-14 Several of these cytokines have been
reported to interfere at different steps of the antitumor immune
response, in particular antigen presentation and CTL differentiation
(for review, see Chouaib et al15).
In the present study, we show that RCC cell lines produce soluble
factors that inhibit the differentiation of CD34+
progenitors into DC and redirect their differentiation towards the
monocyte-macrophage lineage. This phenomenon is shown to be mediated by
IL-6 and macrophage colony-stimulating factor (M-CSF).
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MATERIALS AND METHODS |
Hematopoietic Factors
Recombinant human GM-CSF (rhGM-CSF; specific activity, 2 × 106 U/mg; Schering Plough Research Institute, Kenilworth,
NJ) was used at optimal concentration of 100 ng/mL (200 U/mL), recombinant human tumor necrosis factor (rhTNF; specific
activity, 5 × 106 U/mg; Cetus, Amsterdam, The
Netherlands) at 2.5 ng/mL (50 U/mL), recombinant human stem cell factor
(rhSCF; specific activity, 4 × 105 U/mg;
R&D System, Abingdon, UK) at 25 ng/mL, M-CSF (specific activity, 2 × 106 U/mg; R&D) and IL-6 (specific activity,
106 U/mg; Sandoz, Basel, Switzerland) at 20 ng/mL, and
vascular endothelial growth factor165 (VEGF165)
(R&D) at 25 ng/mL.
Obtention of RCC Conditioned Medium (CM)
RCC lines obtained from ATCC (CAKI-1 and CAKI-2) or generated in the
laboratory (CLB-CAN, CLB-CHA, CLB-GUI, CLB-OTE, CLB-TUG, CLB-TUT, and
CLB-VER; Bain C, et al, manuscript submitted) were plated
in 100-mm diameter dishes at a density of 5 × 105
cells/mL in RPMI 1640 medium supplemented with 2 mmol/L glutamine, 200 UI/mL penicillin, 200 µg/mL streptomycin (GIBCO Laboratories, Grand
Island, NY) and 10% fetal calf serum (FCS; Biowittaker, Verviers,
Belgium). After 2 days of culture, supernatants were harvested,
filtered, aliquoted, and stored at  20°C for further use.
Other tumor cell lines conditioned medium were performed in the same
conditions using neuroblastoma (SHEP, IMR32, CLB-CA, CLB-ES, SKNAS, and
SKNFI), melanoma (CLB-DOR), Burkitt lymphoma (Daudi, Raji, and BJAB),
large lung cell carcinoma (H-322), colon carcinoma (HT-29 and SW620),
or breast carcinoma cell lines (T47-D, MCF-7, and CLB-SAV) obtained
from the ATCC (Rockville, MD) collection or generated in
the laboratory.
Preparation of Cells
DC were generated from CD34+ cells isolated from umbilical
cord blood samples obtained according to institutional guidelines. Cells bearing CD34 antigen were isolated from mononuclear fractions through positive selection by mini MACS (Miltenyi Biotec, Gmbh, Bergisch Gladbach, Germany), using an anti-CD34 monoclonal antibody (MoAb; Immu 133.3; Immunotech, Marseille, France) and goat antimouse IgG-coated microbeads (Miltenyi Biotec, Gmbh).16 In all
experiments, the isolated cells were 80% to 99% CD34+.
CD34+ progenitors were seeded for expansion at 5 × 103 to 104 cells/mL in 24-well
plates in complete medium in the presence of GM-CSF (100 ng/mL), TNF
(2.5 ng/mL), SCF (20 ng/mL), and 2% human serum AB+
(sAB+) as previously described for 6 days.16,17
After 6 days, cells were harvested, numbered, phenotyped, and seeded in
absence of sAB+ but in the presence of GM-CSF and TNF at
5 × 104 cells/mL for 6 additional days, with a last
medium change being performed at day 10. Cells were collected at day
12. Eventually, adherent cells were recovered using a 5 mmol/L EDTA
solution.
Isolation of CD1a+ and CD14+ Precursors by
FACS Sorting
After 6 days of culture in the presence of
GM-CSF+TNF+SCF+sAB+, cells were collected and labeled
with fluorescein isothiocyanate (FITC)-conjugated OKT-6
(CD1a; Ortho, Roissy, France) and phycoerythrin (PE)-conjugated Leu-M3 (CD14; Becton Dickinson, Pont de
Claix, France).
Cells were separated according to CD1a and CD14 expression into
CD1a+CD14 and
CD1aCD14+ fractions using a FACS
Starplus (laser setting: power at 250 mw and excitation wavelength at
488 nm; Becton Dickinson). All the procedures of staining and sorting
were performed in the presence of 5 mmol/L EDTA to avoid cell
aggregation. Reanalysis of the sorted populations showed a purity
greater than 98%.
Sorted cells were seeded in the presence of GM-CSF+TNF with or
without 10% RCC CM (5 × 104 cells/mL) for 6 additional days, with a last medium change being performed at day 10. Cells were then recovered at day 12 and adherent cells were removed
using a 5 mmol/L EDTA solution.
Mixed Lymphocyte Reaction (MLR) Assay
After 12 days of culture, CD34-derived cells were collected and, after
irradiation (30 Gy), used as stimulator cells for allogeneic adult
naive T lymphocytes (CD45RA+) purified from healthy
volunteer peripheral blood mononuclear cells (PBMC) by
immunomagnetic depletion using a cocktail of MoAbs.16 After
two rounds of bead depletion, the purity of CD45RA+ was
routinely higher than 95%. From 17 to 104 stimulator cells
were added to the T cells (2 × 104 cells/well) in
96-well round-bottomed microtest culture plates (Nunc, Rockilde,
Denmark). Cultures were performed in RPMI complete medium supplemented
with 10% FCS. After 5 days of incubation, cells were pulsed with 0.5 µCi of 3HTdR per well (specific activity, 5 mCi/mmol) for
the last 18 hours, harvested, and counted. Tests were performed in
triplicates and results were expressed as the mean counts per minute
(cpm) ± standard deviation (SD). The levels of 3H-TdR
uptake by stimulator cells alone were always less than 100 cpm.
Cell Surface Phenotyping
Cells were processed for double staining at day 6 and day 12 using
anti-CD14-PE (Becton Dickinson) and anti-CD1a-FITC (Coulter Clone,
Marseille, France). Negative controls were performed with unrelated
murine MoAbs. Extensive phenotype were performed at day 12 with
MoAbs-PE. The antibodies used were PE labeled (except when specified)
and purchased from Becton Dickinson for negative control, CD14, CD15,
HLA-DR, CD80, CD16, CD11b; Pharmingen (San Diego, CA) for CD86;
Immunotech for CD23, CD83, CDw116, CD40, CD54, and CD58; Caltag
Laboratories (Burlingame, CA) for CD32, CD64; Ortho
Diagnostic (Raritan, NJ) for CD1a/FITC; and Oncogene Science
(Cambridge, MA) for rat control isotype and CD115 (cfms). Fluorescence
analysis was performed on a FACScan flow cytometer after acquisition of
5,000 events (Becton Dickinson).
Neutralizing Antibodies
MoAb anti-IL-6 (BE-8) and anti-IL-6R (BR-6) were purchased from
Diaclone (Besançon, France). MoAb anti-VEGF and rabbit and mouse
Igs used as control antibodies was purchased from R&D. Polyclonal anti-M-CSF was purchased from Genzyme (Paris, France). All antibodies were used at optimal concentrations (10 to 20 µg/mL).
Cytokine Detection
Cytokines were detected in conditioned media and culture supernatants
using commercial quantitative sandwich immunoassay kits from Immunotech
(IL-6) and R&D System (VEGF and M-CSF).
Phagocytosis
CD34+ cells were cultured in the presence of GM-CSF+TNF
alone or with 10% RCC CM or breast CM for 12 days with or without specific antibodies. During the last 4 hours of the culture, 0.5-µm latex beads coupled to FITC (1/400; Polysciences, Warrington, PA) were
added in the culture. To analyze the phagocytic capacity, cells were
recovered and washed three times in cold phosphate-buffered saline
(PBS), and beads incorporation was evaluated on a FACScan analyzer
(histograms) or observed on a fluorescence microscope after
cytocentrifugation and MGG coloration.
Statistics
Statistical analyses were performed using Fisher's exact test and a
test of comparison of percentages.
| |
RESULTS |
Inhibition of the Differentiation of DC by RCC Medium
Phenotypic modifications.
CD34+ progenitors cultured with GM-CSF+TNF+SCF
differentiate into dendritic cells characterized by the acquisition of
CD1a and the loss of CD14 antigens at day 1216,18,19
(Fig 1). In the presence of 10% final
concentration of RCC CM, cultured CD34+ cells displayed an
altered phenotype at day 12 with a reduced expression of CD1a antigen
(60% CD1a+ with a mean fluorescence intensity [MFI] of
30 in medium alone v 14.6% with an MFI of 5.3 in the presence
of RCC CM), whereas breast carcinoma CM (T47-D or MCF-7) had no effect
(Fig 1). In 28 different experiments, after a 12-day culture period,
50% to 79% of the cells obtained in the presence of 10% RCC CM
expressed CD14 Ag, compared with those cultured in medium or 10% T47-D
CM (Fig 1). Among these different experiments, the median reduction of
CD1a expression induced by the different RCC CM was 69%, with a range
of 32% to 87%. All nine RCC CM tested induced a similar effect (not
shown).
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| Fig 1.
Inhibition of the differentiation of DC from
CD34+ progenitors by RCC CM. CD34+
progenitors were incubated with GM-CSF+TNF alone or in the
presence of 10% of RCC CM or breast CM (control). Medium was replaced
at days 6 and 10. A double staining with CD14-PE and CD1a-FITC
antibodies was performed at day 6. At day 12, cells were labeled with
CD14-PE/CD1a-FITC or CD86-PE/CD1a-FITC and analyzed on a FACScan
(Becton Dickinson). Results are of one representative experiment
performed with different seven CD34+ cells samples.
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In addition, CD34+ cells cultured in the presence of RCC CM
(but not of breast carcinoma CM) displayed an increased expression of
IgG receptor molecules (CD32 and CD64), whereas the expression of
costimulatory molecules (CD80, CD86, and CD40) and HLA-DR was strongly
inhibited (Fig 2). Regarding adhesion
molecules, CD58 expression was weakly inhibited, whereas CD54 was not
significantly affected. CD83, a specific marker for DC,20
and CD116 (GM-CSF receptor chain [GM-CSFR]) normally expressed
on DC generated from CD34+ were absent when cells were
cultured with RCC CM, whereas CD115 (M-CSF receptor [M-CSFR]) was
upregulated (Fig 2). In all culture conditions, no CD15 expression was
observed on cultured CD34+ cells, demonstrating the absence
of granulocytic cells (Fig 2). Altogether, these results demonstrate
that RCC CM profoundly affects the characteristic phenotypic
differentiation of CD34+ progenitors into DC.16
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| Fig 2.
Phenotypic modifications induced by culture with RCC CM
for 12 days. CD34+ cells cultured for 12 days with
GM-CSF+TNF ( ) or in the presence of 10% RCC CM ( ) were
harvested and processed for staining with PE-conjugated MoAbs or
uncoupled MoAb shown by PE-conjugated antirat Ig (CD115). Antimouse
control antibody was shown in the first histogram. Antirat control
antibody overlaps this control (data not shown). Results are
representative of four experiments.
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Cells obtained after 12 days of culture in the presence of RCC CM (Fig
3B and D) were morphologically distinct
from DC (Fig 3A and C) and displayed a macrophage morphology (Fig 3B),
a strong adherence to plastic surface (Fig 3B), small nuclei, and
numerous intracytoplasmic vacuoles (Fig 3D).
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| Fig 3.
Modulation of cell morphology by RCC medium. Cells
cultured from day 6 to day 12 in GM-CSF+TNF alone (a, c, and e) or
in the presence of 10% RCC CM (b, d, and f). Cell morphology as
evaluated by phase contrast microscopy (a and b) and MGG staining (c
and d) and phagocytic capacity (e and f) evaluated by FITC-coupled 0.5 µmol/L latex beads ingestion for the last 4 hours of culture time
(counterstained with MGG). Results are representative of 10 different
experiments.
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The inhibitory effect of RCC CM on CD34+ cells
differentiation was dose-dependent, being detectable at 1% final
concentration and with a maximum inhibitory effect at a 10% final
concentration of RCC CM for the VER cell line
(Fig 4). It is noteworthy that the
magnitude of the effect of RCC CM varied according to the RCC CM
tested. Whereas some RCC CM were found to have a major effect at 2%
final concentration (CLB-TUT, CLB-GUI, and CLB-OTE), for others
(CLB-CAN and CLB-TUG) a 25% final concentration of CM was required to
obtain a similar biological effect. In contrast, none of the breast
carcinoma CM used (T47-D, M-CF7, and CLB-SAV) was able to block DC
differentiation, even when used at high concentration (50% CM; data
not shown).
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| Fig 4.
Dose-dependent inhibition of DC differentiation by RCC
CM. Cells were cultured from day 6 to day 12 in the presence of an
increasing percentage of RCC CM (1% to 20%;  ) or breast CM ( ).
At day 12, cells were harvested and processed for labeling with CD14-PE
( -) and CD1a-FITC () antibodies. Results are representative of five
experiments.
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The differential effect of RCC CM during the expansion (day 0 to 6) and
the maturation phases (day 6 to 12) on the phenotype of cultured
CD34+ cells was then investigated.16 The
addition of RCC CM from day 0 to 12 or during the maturation phase only
(day 6 to 12) inhibited the acquisition of the DC phenotype
(Fig 5). The addition of RCC CM during the
proliferative phase only (day 0 to 6) partially affected CD14 and CD1a
expression on cultured CD34+ cells at day 6 (Fig 5).
However, in this condition, a decrease of CD1a expression intensity was
observed (MFImedium = 96 and MFIRCC CM = 53)
and was associated with an increase of CD14 intensity (MFImedium = 87 and MFIRCC CM = 179; Fig 1);
however, at day 12, the phenotype of cells cultured with RCC CM from
day 0 to 6 only was similar to that of cells cultured without RCC CM
(Fig 5).
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| Fig 5.
Effect of RCC CM during the different phases of the
culture. Double staining (CD14-PE/CD1a-FITC) was performed at day 12 and the results were compared for CD34+ cultured with
cytokines alone (control) or in the presence of 10% RCC CM from day 0 to 6 (top right), from day 6 to day 12 (bottom left), or day 0 to day
12 (bottom right). Results are representative of four experiments.
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Functional modifications.
In addition to these phenotypic alterations, CD34+ cells
cultured with RCC CM displayed important functional alterations. RCC CM
induced an increased proliferation rate (1.5- to 2.3-fold increase) during both the proliferation and the maturation phases with all 9 different RCC cell lines supernatants tested (not shown).
In addition, cells generated in RCC CM exhibited a strong phagocytic
capacity as evaluated by the ingestion of 0.5-µm latex beads coupled
to FITC (Fig 3F) compared with CD34+ cells cultured with
cytokines alone (Fig 3E).
The APC function of CD34+ cells cultured with cytokines
with or without tumor cell medium (RCC CM and breast carcinoma CM) was
evaluated by measuring their capacity to induce the proliferation of
purified naive (CD45RA+) allogeneic CD4+ T
cells in an MLR. Cells obtained from CD34+ progenitor cells
cultured with cytokines in the presence of RCC CM between day 0 and 12 (data not shown) or only during the maturation phase (day 6 to 12) were
found to be unable to stimulate naive T-cell proliferation as compared
with cells generated without RCC CM (Fig
6).
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| Fig 6.
Inhibition of antigen-presenting cell function by RCC CM.
CD34+ cells were cultured from day 0 to 6 in
GM-CSF+TNF. Medium was then changed and the cells were cultured in
the presence of cytokine alone (control; ), RCC CM ([] CLB-VER
CM; [] Caki-1 CM), or breast CM (T47-D CM;  ) from day 6 to 12. Cells were then harvested, irradiated (30 Gy), and used as stimulator
cells for naive T cells (2 × 104 cells/well). The
proliferation was evaluated using 3HTdR uptake after 5 days
of culture. Results are expressed as the mean ± SD of triplicate
culture. These results are representative of five different
experiments.
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These results indicate that RCC CM inhibits the differentiation of
CD34+ cells into DC and triggers their differentiation into
macrophages with a poor APC function but a strong phagocytic capacity.
Effect of RCC CM on the two independent subsets of DC development.
At an early time point (day 6) of culture of CD34+ cells in
GM-CSF+TNF+SCF, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 Ag emerge independently that
correspond to two different pathways of DC development: the Langerhans
cells (CD1a+) and the CD14-derived DC related to dermal DC
or circulating blood DC (CD14+).16
We analyzed the biological effect of RCC CM on these two different
subpopulations. [CD1a+CD14] and
[CD1aCD14+] cells generated from
CD34+ cells cultured in GM-CSF+TNF+SCF were FACS-sorted
at day 6. An additional 6 days of culture of these two populations in
GM-CSF+TNF without RCC CM demonstrate that
[CD1a+CD14] as well as
[CD1aCD14+] were able to differentiate
into DC in terms of phenotype (Fig 7A) and
high APC capacity (Fig 7B), as described previously.16 In
contrast, in the presence of 10% RCC CM, CD1a+-derived DC
failed to acquire expression of CD86 and exhibited lower levels of
HLA-DR expression (Fig 7A). In addition, in an MLR assay, these cells
were unable to induce allogeneic naive T-cell proliferation (Fig 7B).
In the presence of 10% RCC CM, the day-6
[CD14+CD1a] subpopulation also failed
to differentiate into DC but was driven into macrophages (as described
for the nonsorted population) with a specific phenotype
(CD14+,CD1a,HLA-Drlow,CD86;
Fig 7A), a high phagocytic capacity (not shown), and a reduced APC
capacity (Fig 7B).
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| Fig 7.
Cord blood CD34+ cells were cultured for 6 days in the presence of GM-CSF+TNF+ SCF+sAB+.
Cells were then collected, processed for double staining using
anti-CD14-PE and anti-CD1a-FITC, and FACS-sorted into
[CD14+CD1a] and
[CD14CD1a+] populations. Sorted cells
were seeded in the presence of GM-CSF+TNF at 5 × 104
cells/mL for 6 additional days in the presence or absence of RCC CM
(10%), with a last medium change being performed at day 10. (A)
Phenotype of purified populations at day 12. At day 12, cells were
recovered and analyzed for CD1a, CD14, CD86, and HLA-DR expression by
double-color fluorescence. (B) Function of the cells generated. At day
12, cells cultured in the presence of GM-CSF+TNF alone (medium;
) or in the presence of RCC CM () were recovered, numbered,
irradiated (30 Gy), and used as stimulator cells (3.3 × 103 cells/well) in an MLR with naive
CD45RA+ T cells (2 × 104 cells/well).
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These results are consistent with those observed with the bulk
population and demonstrate that RCC CM blocks both pathways of DC
differentiation.
Effects of RCC CM Is Mediated by IL-6 and M-CSF
RCC cell lines produce a wide range of cytokines, including
GM-CSF,14 TGF,14 IL-612,13
(Table 1), M-CSF (Table 1), and VEGF
(range, 2.7 to 6.2 ng/106 cells/48 hours in the 9 RCC cell
lines) that could potentially act on DC differentiation. Because GM-CSF
and TGF are well known inducers of DC differentiation in
vitro,21 we examined whether M-CSF, IL-6, or VEGF could be
responsible for the inhibitory effects of RCC CM on DC
differentiation.22-26 The effects of antibodies against
M-CSF, IL-6, or VEGF during the differentiation phase (day 6 to 12)
were investigated. CD34+ cells were precultured for 6 days
(day 0 to 6) in the presence of GM-CSF+TNF+SCF+sAB+ and
then incubated with GM-CSF+TNF and 10% RCC CM in presence of
neutralizing antibodies anti-VEGF, anti-IL-6/IL-6R
(anti-IL-6+anti-gp80/IL-6R), or anti-M-CSF from day 6 to 12. As
shown in Fig 8, anti-IL-6/IL-6R and
anti-M-CSF partially reversed the phenotypic modifications induced by
RCC CM in terms of CD14 expression, whereas control antibodies (mouse
IgG or total rabbit Ig) had no effect. Anti-IL-6 or anti-IL-6R alone
had similar but weaker effects (not shown). Anti-M-CSF alone partly
reversed the effect of RCC CM on CD1a blockade. The combination of
anti-IL-6/IL-6R with anti-M-CSF completely reversed the effects of
RCC CM on the phenotype of cultured CD34+ cells in terms of
CD14 and CD1a expression (Fig 8), CD116 and CD115 expression
(Table 2), and CD80, CD86, and HLA-DR
expression (not shown).
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| Fig 8.
Inhibition of CD34+ cell differentiation
into DC is mediated by IL-6 and M-CSF. These results are expressed as
the percentage of CD14+ and CD1a+ cells.
CD34+ cells were cultured with GM-CSF+TNF alone
( ) or in the presence of 10% CLB-VER CM ( ) from day 6 to 12. Neutralizing antibodies were added alone or in combination at 10 µg/mL. At day 12, cells were harvested and processed for double
labeling with CD14-PE and CD1a-FITC. For all conditions, the SD ranged
from 1% to 2%. *P < .01 as compared with RCC CM-treated
cells.
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Anti-IL-6/IL-6R and anti-M-CSF abrogated the inhibitory effects of
RCC CM on the reversed APC function of cultured CD34+ cells
(Table 3). Anti-IL-6/IL-6R and anti-M-CSF
also reversed the increase of phagocytic capacity of cultured
CD34+ cells induced by RCC CM
(Table 4). In contrast, an anti-VEGF antibody did not affect the phenotype (Fig 8) and the function (Table
3) of CD34+ cells cultured with RCC CM.
To confirm the role of IL-6 and M-CSF, CD34+ cells were
cultured from day 6 to 12 in the presence of recombinant IL-6 (20 ng/mL), M-CSF (20 ng/mL), and VEGF (25 ng/mL) alone or in combination. Exogenous IL-6 and/or M-CSF mimicked the effect of RCC CM in
terms of CD14/CD1a modifications (Fig 9) as
well as CD80, CD86, HLA-DR, and CD116 expression and cell morphology
(not shown), phagocytosis (Table 4), and APC function
(Fig 10). Anti-IL-6/IL-6R reversed the
effects of both IL-6 and M-CSF in terms of CD14/CD1a phenotype, phagocytic capacity, and APC function. In contrast, anti-M-CSF only
slightly interfered with the biological effects of IL-6 in terms of
CD14/CD1a phenotype (Fig 9), phagocytic function (Table 4), and APC
function (Table 3). Titration performed with recombinant cytokines
alone or in combination demonstrates that the minimal concentration of
recombinant IL-6 or M-CSF required to induce an effect on DC
differentiation was 1 ng/mL and 500 pg/mL for their combination (data
not shown).
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| Fig 9.
Inhibition of CD34+ cell differentiation by
IL-6 and M-CSF. CD34+ cells were cultured with
GM-CSF+TNF alone (control) or in the presence of 10% CLB-VER CM,
IL-6 (20 ng/mL), M-CSF (20 ng/mL), or VEGF (25 ng/mL) from day 6 to 12. Neutralizing antibodies ([] control antibodies), ( )
anti-IL-6+IL-6R, () anti-M-CSF, or () the combination of
anti-IL-6+IL-6R and anti-M-CSF were added at 10 µg/mL in the
culture. At day 12, cells were harvested and processed for a double
staining with CD14-PE and CD1a-FITC. Results are expressed as the
percentage of CD14+ and CD1a+ cells. For
all conditions, the SD ranged from 1% to 2%.
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| Fig 10.
Inhibitory effect of IL-6 and M-CSF on APC function.
CD34+ cells were cultured from day 6 to day 12 with
GM-CSF+TNF alone () or in the presence of exogenous cytokines
() IL-6 (20 ng/mL), ( ) M-CSF (20 ng/mL), () VEGF (25 ng/mL),
or () Caki-1 CM (10%) alone. Cells generated were harvested at day
12, irradiated (30 Gy), and used as stimulator cells (17 to
104 cells) in an allogeneic MLR with CD45RA+
naive T cells (2 × 104 cells/well) as described above.
Results are representative of five experiments.
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It is noteworthy that recombinant M-CSF (20 ng/mL) induced IL-6
production by cultured CD34+ cells at day 12 (with medium
alone, <7.5 pg/mL; with M-CSF, 1.41 ± 0.46 ng/mL in a
representative experiment), whereas IL-6 (20 ng/mL) did not affect
M-CSF production at day 12, suggesting that M-CSF acts in part by
inducing a secondary IL-6 production. These results demonstrate
that IL-6 and M-CSF are responsible for the blockade of DC generation
from CD34+ cells induced by RCC CM.
Modulation of GM-CSFR (CD116) and M-CSFR (CD115) Expression on
CD34+ Cells by RCC CM, IL-6, and M-CSF
We asked whether the inhibitory effect of RCC CM on CD34+
cell differentiation into DC could result from a modulation of CD116 expression. Indeed, RCC CM as well as recombinant M-CSF (Table 2) were
found to completely inhibit the expression of CD116 at the surface of
CD34+ cells. Recombinant IL-6 also inhibited CD116
expression, although only partially (Table 2). Anti-M-CSF abrogated
the inhibitory effect of RCC CM on CD116 expression. Conversely, RCC
CM, recombinant IL-6, and recombinant M-CSF were found to induce an
upregulation of CD115 expression at the surface of cultured
CD34+ cells (Table 2); the combination of recombinant IL-6
and M-CSF exerted an additive effect on CD115 expression (Table 2).
Anti-IL-6/IL-6R and anti-M-CSF additively blocked the induction of
CD115 expression induced by RCC CM (Table 2). Taken together, these
results demonstrate that the inhibition of CD34+ cells
differentiation into DC by RCC CM, recombinant M-CSF, and/or recombinant IL-6 is associated by a downregulation of GM-CSFR expression and the induction of M-CSFR expression.
Correlation Between IL-6 and M-CSF Production and the Inhibition of
DC Development in a Panel of Tumor Cell Lines
The supernatants of a panel of tumor cell lines of various histologies
(melanoma, lymphoma, breast carcinoma, neuroblastoma, large cell lung
carcinoma, and colon carcinoma) were tested for their capacity to block
CD34+-derived DC generation and to produce IL-6 and M-CSF.
As shown in Table 1, the inhibition of DC differentiation, as evaluated by the modulation of CD1a and CD14 expression, by tumor cell
supernatant was highly correlated to IL-6 production (>300 pg/mL; 11 of 14 v 0 of 11;  2 test, P = 104) or M-CSF production (>300 pg/mL; 12 of 14 v 1 of 11; 2 test, P = 2 × 104) by tumor cells. This indicates that a wide
range of tumor cell types are capable of blocking the differentiation
of DC from CD34+ cells and that this effect is strongly
correlated to the production of IL-6 and M-CSF.
| |
DISCUSSION |
The results presented here show that RCC cell lines produce soluble
factors that inhibit the differentiation of DC from CD34+
progenitor cells induced by GM-CSF+TNF+SCF, in particular the acquisition of the characteristic differentiation Ag of DC (ie, CD1a,
CD80, CD83, CD86, HLA-DR, and CD40...) as well as the acquisition of the APC function as evaluated by their capacity to trigger the
proliferation of naive allogeneic CD4+ T lymphocytes.
Similar inhibitory effects were observed when RCC CM was added in the
culture from day 0 to 12 or only during the differentiation period (day
6 to 12).
Two different pathways of DC differentiation from CD34+
progenitors have been previously described in this culture
system,16 involving the two different populations
detectable at day 6 ([CD14+CD1a] and
[CD14CD1a+]). The inhibitory effect of
RCC CM on DC differentiation on the unsorted population at day 6 was
also observed on sorted day-6 [CD14+CD1a] cells. In addition, RCC CM
blocked the maturation of [CD1a+CD14]
early differentiated from CD34+ cells in terms of
both phenotypic and APC capacity. RCC CM therefore blocks the two
pathways of DC differentiation involving the
[CD14+CD1a] and
[CD14CD1a+] subpopulations at day 6.
The magnitude of the effects of RCC CM varied considerably among
CD34+ cells obtained from different cord blood donors. As
demonstrated previously,16 the respective levels of these
two subpopulations, ie, [CD14+CD1a]
and [CD14CD1a+], emerging at day 6 varied from 12% to 33% for CD14+ subpopulation and 8% to
32% for CD1a+ subpopulation. The variations of the
magnitude of the inhibitory effect of RCC CM on DC differentiation are
likely to result mostly from the variations relative proportion of
[CD14+CD1a] and
[CD14CD1a+] at day 6, a parameter that
is not significantly affected by RCC CM in these experiments.
In the presence of RCC CM, an increased cell yield was observed as
compared with that observed in cytokines alone. However, the observed
decrease of CD1a+ fraction did not result from the
overgrowth of this population by CD14+ cells; indeed, the
quantification of the absolute number of CD1a+ and
CD14+ cells with or without RCC CM in five different
experiments showed a twofold to threefold decrease of the total CD1a
cell number in the presence of RCC CM and, conversely, a 20-fold
increase of the CD14+ population in the same conditions
(data not shown). This could result from the capacity of
CD14+ cells to respond to M-CSF signal, whereas
CD1a+ cells that do not express M-CSFR are unable to
respond to M-CSF.16 Taken together, these results indicate
that RCC CM inhibits the differentiation of CD1a cells and induces a
functional impairement of the remaining CD1a+ cell
population obtained in these conditions.
The results presented here show that tumor cell lines inhibiting DC
development produced high IL-6 and/or M-CSF and that the inhibitory effects of RCC CM on the phenotype, APC functions, and
phagocytic capacity of cultured cord blood cells were reversed by
anti-IL-6/IL-6R and anti-M-CSF antibodies. In addition, recombinant IL-6 with or without recombinant M-CSF was found to mimick the effects
of RCC CM. Actually, IL-6 and M-CSF were found to exert distinct and
additive inhibitory effects on the phenotypic and functional
differentiation of CD34+ progenitors into DC.
Regarding phenotypic modifications, anti-IL-6/IL-6R partially blocked
the induction of CD14 antigen expression induced by RCC CM, whereas
anti-M-CSF reversed partly the effects of RCC CM on both CD14 and CD1a
expression. Importantly, the combination of anti-IL-6/IL-6R and
anti-M-CSF additively and completely reversed the phenotypic
modifications induced by all RCC CM on cultured CD34+
cells. High concentrations of recombinant IL-6 and M-CSF were capable
of exerting similar inhibitory effects on the phenotypic differentiation of CD34+ cells, indicating that both
cytokines are involved in the phenotypic alterations induced by RCC CM.
It is noteworthy that the phenotypic modifications induced by
recombinant M-CSF were also inhibited by anti-IL-6/IL-6R antibodies.
Because M-CSF induced IL-6 production in these culture conditions,
these results suggest that IL-6 is also a second mediator of M-CSF
activity in this model.
CD34+ cells cultured in the presence of RCC CM were found
to have characteristic features of macrophages in terms of morphology and function, with a high phagocytic capacity and poor APC function. Here also, both M-CSF and IL-6 contributed to this phenomenon. Anti-IL-6/IL-6R antibodies reversed partially the effects of the RCC
CM on the phagocytic activity and APC function of cultured CD34+ cells. Anti-M-CSF antibody also partially reversed
the inhibitory effect of RCC CM on APC function of cultured
CD34+ cells. The combination of anti-IL-6/IL-6R and
anti-M-CSF additively reversed the effects of RCC CM on the APC
function of cultured CD34+ cells. However, with all cell
lines tested, anti-M-CSF alone was found capable of completely
inhibiting the increased phagocytic capacity induced by tumor cell
medium, indicating that M-CSF plays a predominant role in the
acquisition of high phagocytic function by CD34+ cells.
Finally, IL-6 and M-CSF exerted distinct effects on the expansion of
cultured CD34+ cells costimulated with GM-CSF and TNF.
The increased proliferation induced by RCC CM was found to be mediated
by M-CSF because (1) anti-M-CSF, but not anti-IL-6/IL-6R, reversed
this effect and (2) recombinant M-CSF, but not recombinant IL-6,
exerted a similar proliferative effect (not shown). This result is in
agreement with those reported by Szabolcs et al17
demonstrating the capacity of CD14+ subpopulation to
proliferate in the presence of M-CSF.
These results are consistent with previous reports showing that IL-6
plays an important role in the monocytopoiesis from myeloid progenitors, that M-CSF induces the differentiation of
CD34+ pluripotent cells into
macrophages,17,22,23,25,27 and that IL-6 synergizes with
M-CSF for the formation of macrophage colonies from purified
CD34+ progenitors.24 In addition, anti-IL-6
has been reported to inhibit the generation of colony-forming
unit-macrophages (CFU-M) induced by M-CSF from bone
marrow precursors.25 However, our results are in contrast
with a recent study28 demonstrating that production of high
levels of IL-6 (500 to 700 pg/mL; probably by cogenereated monocytes)
during DC development from CD34+ progenitors in
GM-CSF+TNF+SCF+sAB+ contributed to increase the yield of
DC. Although differences in culture conditions may account for this
discrepancy, the most likely explanation may be that the levels of IL-6
described by these investigators are under those required with
recombinant IL-6 alone to block DC differentiation. It is noteworthy
that the presence of M-CSF in culture medium was not reported in this study.
Taken together, these results demonstrate that IL-6 and M-CSF produced
by RCC cells cooperate for the inhibition of the generation of DC from
CD34+ cells induced by RCC CM. These results also show that
IL-6 and M-CSF redirects the differentiation of these cells towards
macrophage lineage. It must be noted that the capacity of
anti-IL-6/IL-6R versus anti-M-CSF to reverse the biological effects
of RCC CM on CD34+ cell differentiation varied according to
the tumor cell line studied and their respective levels of IL-6 and
M-CSF production. It is also important to note that the concentrations
of exogenous recombinant IL-6 or M-CSF required to block DC
differentiation were twofold to 10-fold higher than those present in
10% RCC CM for some RCC cell lines (CLB-CAN and CLB-TUG). This
discrepancy suggests that another soluble factor(s) produced by some
RCC cell lines may cooperate with IL-6 and/or M-CSF to inhibit
DC differentiation.
The results presented here indicate that the molecular mechanisms by
which RCC CM antagonize the effects of the GM-CSF+TNF combination
involve the modulation of GM-CSF and M-CSF receptors expression (CD116
and CD115, respectively) at the surface of cultured CD34+
cells. RCC CM, recombinant IL-6, and, to a lesser extent, recombinant M-CSF were found to induce an increase of M-CSFR expression at the
surface of differentiating CD34+ cells; the induction of
CD115 expression by RCC CM is blocked additively by anti-IL-6/IL-6R
and anti-M-CSF, a result consistent with previous publications on
monocytes.24 Conversely, RCC CM, recombinant
M-CSF, and, to a lesser extent, recombinant IL-6 induced a
downregulation of GM-CSFR expression. The loss of CD116 and the
acquisition of CD115 expression was found to be an early event during
CD34+ cell culture, being detectable at day 8, ie, 2 days
after the addition of tumor cell medium to CD34+ cell
culture (not shown). The loss of GM-CSFR expression may render
CD34+ cells completely insensitive to the effect of GM-CSF,
which is absolutely required for DC differentiation in this model (for review, see Caux and Banchereau29). In contrast, the
induction of M-CSFR expression is likely to contribute to support the
differentiation of [CD14+CD1a] cells
towards the macrophage lineage.
Preculture of CD34+ cells from day 0 to 6, ie, during the
early phase of DC differentiation, induced phenotypic modifications that were completely reversed by an additional 6 days of culture in
GM-CSF+TNF alone. The reversibility of the inhibitory effect of
M-CSF on DC differentiation in the early phases of the differentiation process has also been reported by Chapuis et al.30 However, in the present work, it is also clear that the inhibitory effect of
IL-6 and/or M-CSF is not reversible after 12 days of culture. We observed that CD34+ cord blood cells cultured from day 0 to 12 or only during the maturation period (day 6 to 12) with RCC CM
failed to acquire a DC phenotype or function after additional culture
between day 12 and 18 in the presence of GM-CSF+TNF or GM-CSF+IL-4
(data not shown), demonstrating that macrophages obtained at day 12 were terminally differentiated. This result is also consistent with
those described by Szabolcs et al17 demonstrating that day-12 macrophages generated in M-CSF from day-6 CD14+
intermediates could not become DC even if recultured in GM-CSF+TNF.
Several other cytokines have been described to block DC differentiation
and functions, in particular VEGF, which is produced at high levels by
tumoral cells.26 Although RCC cells produced high levels of
VEGF (range, 2.7 to 6.2 ng/mL/106 cells/48 hours in the 9 different cell lines tested), the addition of neutralizing anti-VEGF
antibody did not reverse the blocking effects of RCC CM on DC
differentiation. Moreover, the addition of exogenous VEGF (25 ng/mL)
during the differentiation phase (day 6 to 12) did not affect DC
differentiation. This discrepancy could result from the fact that VEGF
acts at very early stages of DC differentiation (D. Gabrilovich,
personal communication, March 1998), whereas here the effects of VEGF
were tested between day 6 and 12.
IL-10 has also been reported to inhibit DC differentiation and
function. IL-10 was reported to block the differentiation of monocytes
into DC31,32 and to inhibit the APC function of epidermal Langerhans cells33-35 and of monocyte- and
CD34+-derived DC.36-39 However, none of the RCC
cell lines tested here was found to produce detectable IL-10
levels,40 and IL-10 was not found in the culture
supernatants even at day 7 to 9 (not shown). Finally, the use of
anti-IL-10 neutralizing antibody did not modify the blocking effect of
RCC CM on DC differentiation. This demonstrates that IL-10 is not
involved in the inhibitory effects of tumor cell medium described in
this study, in contrast with what is observed for
monocytes.40
Interestingly, the important role of IL-6 observed in the present
report is in agreement with previous clinical observations made in
patients treated with IL-2. The presence of high pretreatment serum
IL-6 levels has been found inversely correlated to the response to IL-2
and to survival after immunotherapy with IL-2 in patients with
RCC41 as well as in melanoma and colorectal
carcinoma.42,43 Although the correlation between high serum
IL-6 levels and survival could result from the deleterious effects of
this cytokine on the general status of these patients,44-46
the biological explanation for the inverse correlation with response to
IL-2 in several different human tumors was unclear. The present results
suggest that these clinical observations may result from the
immunosuppressive role of IL-6 on DC differentiation. In the present
study, a wide range of tumor cells lines were found capable to produce
IL-6 and M-CSF and to block DC differentiation, indicating that the
production of IL-6 may be a frequent phenomenon by which tumor cell may
protect themselves against the antitumor immune response.
Interestingly, the overproduction of IL-6 has been found correlated
with a defective immunity in vivo in other diseases, in particular in
acquired immunodeficiency syndrome (AIDS) patients.47 The
immunosuppressive role of IL-6 described here may account, at least in
part, for this observation.
In conclusion, these results indicate that RCC cells inhibit the
differentiation of CD34+ cells into DC through an
IL-6- and/or M-CSF-dependent mechanism. These results
undercover a frequent mechanism by which tumor cell may inhibit the
spontaneous and therapeutic antitumor immune response and may account
for the inverse correlation between in vivo IL-6 production and immune
status in cancer and infectious diseases in humans.
| |
ACKNOWLEDGMENT |
The authors are grateful to I. Durand for FACS-sorting; to A. Duc, I. Iacono Di Cacito, and C. Massacrier for their technical assistance; and
to the doctors and colleagues from clinics and hospitals in Lyon who
provided us with the umbilical cord blood samples.
| |
FOOTNOTES |
Submitted January 14, 1998;
accepted August 11, 1998.
Supported by grants from Le LIONS Bourg Doyen, Le Comité de
Saône et Loire and le comité du Rhône de La Ligue
Contre le Cancer, la Ligue Nationale Contre le Cancer and l'ARC.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to J.Y. Blay, MD, PhD, Unité
"Cytokines et Cancers," Unité Inserm 453, Centre Léon
Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, France;
e-mail: blay{at}lyon.fnclcc.fr.
| |
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Top
Abstract
Introduction