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*
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612; and
Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, IL 60153
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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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and IL-10 (3). Another possible mechanism is an
effect induced by accumulation of immature myeloid cells in
tumor-bearing hosts. Several groups have reported an increased
production of these cells capable of inhibiting T cell functions in
cancer patients and tumor-bearing mice (4, 5, 6, 7, 8). In mice,
recently these immature myeloid cells were more precisely characterized
as Gr-1+ cells. Increased presence of these cells
has been described in bone marrow and spleens of tumor-bearing mice
(9, 10, 11). These cells express the Mac-1 (CD11b) marker of
myeloid cells and are able to cause a significant decrease in CD3
molecule expression in T cells, which is important for signal
transduction (9). It is possible that
Gr-1+CD11b+ cells play an
important role in T cell deficiency in cancer. However, it is not clear
how these cells could affect T cell function. In particular, it is not
known whether Gr-1+ cell-mediated inhibition of T
cells is Ag-specific. In this study we have investigated the mechanism
of Gr-1+ cell-mediated inhibition of T cell
functions. We demonstrate that Gr-1+ cells
inhibit Ag-specific CD8-, but not CD4-mediated T cell responses. This
inhibition is dependent on MHC class I expression on the
Gr-1+ cells and could be reversed by
differentiation of these cells in the presence of growth factors and
differentiation agents. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c and C57BL/6 mice (6–8 wk old) were purchased from
Harlan (Indianapolis, IN) and were housed in specific pathogen-free
units of the Division of Comparative Medicine at Loyola University
Medical Center. TCR-transgenic mice expressing an 
TCR specific
for aa 110–120 from influenza hemagglutinin
(HA)3 presented by
I-Ed were a generous gift from Harald von Boehmer
(Basel Institute for Immunology, Basel, Switzerland)
(12). These mice were crossed to a BALB/c background for
>10 generations. Transgenic mice used in these experiments were
heterozygous for the transgene.
Tumor models
MethA sarcoma is a transplantable 3-methylcholanthrene-induced sarcoma of BALB/c origin passaged as an ascitic tumor (13). MethA sarcoma is a relatively immunogenic tumor that carries a carcinogen-induced mutant endogenous p53 gene. MHC class I-restricted peptide (KYICNSSCM) derived from mutant p53 is specific for this model (13, 14). Immunization of mice with this peptide results in tumor protection and partial regression of established tumor. The wild-type p53 counterpart (KYMCNSSCM) does not induce antitumor response and has been used as a control peptide. C3 tumor cell line was made by transfection of C57BL/6 B6 mouse embryonic cells with EJ-ras and plasmid containing the human papillomavirus (HPV) type 16 (15). This is a poorly immunogenic tumor. MHC class I-restricted HPV-16-derived peptide RAHYNIVTF expressed by this tumor was shown to elicit potent anti-tumor immune response (16).
Immunization protocol
The Helios gene gun system (Bio-Rad, Hercules, CA) was used for intradermal gene delivery. A DNA construct containing the H2Db restricted dominant HPV16E7 peptide RAHYNIVTF was used in this study (35). Bullets containing 2 µg DNA per shot were generated according to the manufacturer’s protocols. Briefly, 100 µg DNA was precipitated on 25 mg 1-µm gold particles in the presence of 100 µl 0.05 M spermidine (Sigma, St. Louis, MO) using 100 µl 1 M CaCl2. The particles were washed three times with 1 ml 100% ethanol and resuspended in 3 ml 0.1 mg/ml polyvinylpyrrolidone (PVP) in 100% ethanol. The gold was then loaded into the tubing using the tubing prep station (Bio-Rad), and the gold-loaded tubing was cut into 0.5-inch pieces, then loaded into the cartridges. C57BL/6 mice were anesthetized by i.p. injection of 2.4 mg ketamine (Abbott Laboratories, Abbott Park, IL) mixed in 80 µl PBS with 0.48 mg xylazine (Sigma). The abdominal area was shaved and the DNA was delivered with the gene gun into the epidermis at a helium pressure of 450 psi. This procedure was repeated 2 wk after the first DNA delivery.
Reagents
The following Ab-producing hybridomas were obtained from
American Type Culture Collection (ATCC, Manassas, VA) and used as
culture supernatants: anti-CD4 (L3T4, TIB-207), anti-CD8
(Lyt-2.2, TIB-210), anti-MHC class II (I-Ad,
TIB-120). Mouse GM-CSF, IL-4, and TNF- were obtained from Research
Diagnostics (Flanders, NJ); Con A, all-trans retinoic
acid (ATRA), and polyclonal anti-mouse Ig were obtained from Sigma;
and purified anti-Gr-1, anti-TER-119, FITC- or PE-conjugated
anti-Gr-1, CD11c, CD11b, CD86 (B7-2), I-Ab,
and IAd Abs were purchased from PharMingen (San
Diego, CA). Isotype-matched FITC- and PE-conjugated IgG was used as a
control of nonspecific binding. Low-Tox-M complement and Lympholyte-M
were obtained from Cedarlane Laboratories, (Hornby, Ontario, Canada).
Cell culture inserts with a pore size of 0.2 µm were obtained from
Nolgene. Complete culture medium included RPMI 1640 supplemented
with 10% FCS, antibiotics, and 5 x
10-6 2-ME.
Cell separation and analysis of cell surface receptors
A single cell suspension was prepared from spleens and inguinal, axillary, and brachial lymph nodes, and red cells were removed by hypotonic shock using ACK lysis buffer. For analysis of cell surface receptors, cells were washed in PBS supplemented with 0.1% FCS and labeled with appropriate Abs for 30 min at 4°C. Cells were then washed and analyzed on FACSCalibur flow cytometer (Becton Dickinson, Mountain View, CA). Cell sorting was performed on a FACStar flow cytometer (Becton Dickinson). Macrophages were isolated from spleens of control mice. Briefly, splenocytes were cultured overnight in complete medium, nonadherent cells were removed, and adherent cells were dislodged using a cell scraper. Cells were washed and then used in experiments. An enriched population of T cells was obtained from lymph nodes by incubating cells on ice for 30 min with anti-MHC class II mAb (TIB-120) and polyclonal rabbit anti-mouse Ig. Cells were then washed and incubated with Low-Tox-M complement for 60 min at 37°C. Dead cells were removed by gradient centrifugation on Lympholyte-M.
Ag-specific proliferation
Splenocytes or lymph node cells (105/well) from transgenic mice were mixed with Gr-1+ cells from MethA sarcoma-bearing BALB/c mice in the presence of Con A or synthetic HA peptide (aa 110–120, SFERFEIFPKE) and cultured for 3 days. Eighteen hours before harvesting, cells were pulsed with [3H]thymidine (1 µCi/well; Amersham, Arlington Heights, IL). [3H]Thymidine uptake was counted using a liquid scintillation counter and expressed as cpm.
Enzyme-linked immunospot (ELISPOT) assay
The number of IFN-
-producing cells was measured using an
ELISPOT assay. Briefly, Millipore MultiScreen-HA plates were coated
with anti-mouse IFN- Ab (PharMingen). Splenocytes (2 x
105 cells/well) were cultured for 24 h at
37°C in 5% CO2 incubator in the complete
medium alone or in the presence of the specific or control peptides at
a concentration of 10 µM. After that time, wells were washed and then
incubated overnight at 4°C with a different clone of biotinylated
anti-IFN- Ab (PharMingen). Reactions were visualized using
avidin-alkaline phosphatase and 5-bromo-4-chloro-3-indolyl
phosphate/nitroblue tetrazolium (BCIP/NBT) substrate. The number of
spots per 106 splenocytes, which represented the
number of IFN--producing cells, was calculated blindly by two
investigators.
IL-2 ELISA
ELISA was performed using Abs and protocol developed by PharMingen. The sensitivity of the assay was 6 pg/ml.
Statistical methods
Statistical analysis was performed using parametric methods and JMP statistical software (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Most of Gr-1+
cells (86.2 ± 8.7%) from control mice expressed MHC class I
molecules (H2Dd), and 36.7 ± 5.8% of these
cells were also MHC class II positive (IAd) (Fig. 1). A slightly lower proportion of Gr-1+ cells
from tumor-bearing mice was MHC class I positive (67.3 ± 6.8%,
p > 0.05), and only a minor part (11.9 ± 3.5%)
of Gr-1+ cells from tumor-bearing mice expressed
MHC class II molecules (Fig. 1). These cells did not express markers of
progenitor or stem cells (CD34 and Sca-1; data not shown). Similar
results were obtained from mice bearing C3 tumors (data not shown).
Thus, production of Gr-1+ cells was significantly
increased in tumor-bearing mice. These cells, similarly to
Gr-1+ cells from control mice, were CD11b and MHC
class I positive. However, most of these cells were MHC class II
negative.
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Gr-1+ cells were isolated from spleens of
tumor-bearing mice using cell sorting. First, we measured the effect of
these cells on Con A-induced T cell proliferation.
Gr-1+ cells were incubated with syngenic control
splenocytes and Con A. Gr-1+ cells alone did not
proliferate either spontaneously or in response to Con A (Fig. 2A). In both
experimental tumor models, the presence of Gr-1+
cells in cell culture at a Gr-1+
cells:splenocytes ratio as high as 1:1 did not affect response of
control T cells to Con A (Fig. 2, A and B).
Effect of Gr-1+ cells on T cells might depend on
time of exposure. To test this possibility, splenocytes from control
C57BL/6 mice were cultured overnight with Gr-1+
cells obtained from C3 tumor-bearing mice at a 1:1 ratio. After that
time cells were stimulated with Con A and proliferative response was
measured using [3H]thymidine uptake. This
extended incubation of splenocytes with Gr-1+
cells did not affect T cell proliferation (data not shown). To verify
the effect of Gr-1+ cells on T cell function, we
measured IL-2 production by T cells in response to Con A. Splenocytes
isolated from control C57BL/6 mice were cultured at concentration
5 x 105cells/ml with different numbers of
Gr-1+ cells in the presence of 1 µg/ml Con A.
After 48-h incubation IL-2 was measured in supernatants using ELISA.
Gr-1+ cells did not inhibit Con A-inducible IL-2
production by T cells. At the highest ratio (1:1)
Gr-1+ cells stimulated Con A inducible, but not
spontaneous IL-2 production by T cells (Fig. 2C).
Gr-1+ cells alone did not produce a detectable
amount of IL-2 with or without Con A (data not shown).
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TCR
specific for aa 110–120 from influenza HA presented by MHC class II
(IEd). T cells from these mice demonstrated a
high level of a proliferative response to the specific HA peptide in
vitro (17, 18). Lymph node cells isolated from these
transgenic mice were cultured with Gr-1+ cells
and specific peptide. Gr-1+ cells at ratio as
high as 1:1 did not affect peptide-specific T cell proliferation (Fig. 3, A and
B). No significant effect of
Gr-1+ cells on peptide-specific IL-2 production
was found at ratios from 1:10 to 1:2. However,
Gr-1+ cells stimulated IL-2 production in
response to the specific peptide at ratio 1:1 (Fig. 3C).
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Tumor-induced Gr-1+ cells inhibit CD8-mediated T cell response
Next, we asked whether Gr-1+ cells were able
to affect Ag-specific CD8-mediated response. BALB/c mice were immunized
s.c. twice within a 2-wk interval with mutant p53 peptide in incomplete
Freund’s adjuvant. This peptide is presented by MHC class I. Ten days
after the second injection mice were sacrificed and splenocytes were
stimulated with control or specific peptides in the presence of
Gr-1+ cells isolated from MethA sarcoma-bearing
mice. The number of IFN--producing cells was analyzed using an
ELISPOT assay. An almost 3-fold increase in the number of these cells
was detected in response to the specific peptide. However, the presence
of Gr-1+ cells at a Gr-1+
cell:splenocyte ratio of 1:10 completely abrogated this increase (Fig. 4A). To
confirm this effect in a different strain of mice and different tumor
model, C57BL/6 mice were immunized with DNA encoding the
H2Db-restricted HPV16E7-specific peptide as
described in Materials and Methods. Ten days after the last
immunization the mice were sacrificed, and their splenocytes were
collected and incubated with control or specific peptides in the
presence of Gr-1+ cells isolated from syngeneic
tumor-bearing mice. Incubation of splenocytes with the specific peptide
significantly increased the number of IFN--producing cells. The
presence of Gr-1+ cells at a concentration as low
as 2.5% significantly decreased that number and at a concentration of
5% completely eliminated peptide-specific response (Fig. 4B). To investigate whether the same effect can be observed
in vivo, 3 x 105
Gr-1+ cells isolated from tumor-bearing mice were
pulsed with control or specific peptide for 2 h, washed, and
injected i.v. into immunized C57BL/6 mice. Injections were repeated the
next day and 24 h later mice were sacrificed, and
splenocytes were isolated and stimulated with control or specific
peptides in an ELISPOT assay. Mice treated with
Gr-1+ cells loaded with the specific, but not
with control peptide almost completely blocked T cell response to the
specific peptide as measured in the ELISPOT assay (Fig. 4C).
To exclude the possibility that peptide nonresponsiveness was due to
general suppression of T cell function, splenocytes obtained from the
same treated mice were stimulated with Con A. Splenocytes from all mice
responded equally well to Con A (Fig. 4D). These data
indicate that Gr-1+ cells inhibited
peptide-specific CD8-mediated immune responses in vitro and in
vivo.
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We asked whether the described effects of
Gr-1+ cells might be mediated by soluble factors.
To test this possibility Gr-1+ cells were
cultured for 24 h at 37°C at a concentration 10 times higher
than that used in previous experiments (106
cells/ml). Conditioned media were collected and added to splenocytes
from immunized control mice. Presence of Gr-1+
cell-conditioned media at a concentration as high as 20% did
not affect T cell response to the specific peptide (Fig. 5A). Similar
results were observed when conditioned media were obtained from
Gr-1+ cells stimulated with 10 µM specific
peptide (data not shown). Because many soluble factors able to affect
CD8+ T cells are short-lived, another set of
experiments has been performed. Gr-1+ cells
(2 x 104 cells per well) were placed on top
of semi-permeable membrane (pore size 0.2 µm). Splenocytes from
immunized mice (105 cells per well) were placed
in the bottom chamber of a 96-well plate. Cells were cocultured in the
presence of the specific peptides for 24 h, and an ELISPOT assay
was performed as described in Materials and Methods. No
inhibition of IFN- production was detected under these experimental
conditions (Fig. 5B).
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C).
The effect of LMMA was more prominent with increased numbers of
Gr-1+ cells. This suggests that NO production is
involved in Gr-1+ cell-mediated inhibition of T
cell responses. As we demonstrated above, a substantial proportion of
tumor-induced Gr-1+ cells expressed MHC class I
molecules, but were negative for MHC class II. To investigate possible
involvement of MHC class I in the described inhibition of T cell
response, Gr-1+ cells from tumor-bearing C57BL/6
mice (H2Db) were incubated on ice for 30 min with
3 µg of either specific anti-H2Db Ab or
control anti-H2Dd Ab. After that time cells
were washed and incubated at 37°C for 1 h in complete culture
medium to allow for internalization of the specific molecules. Cells
were then washed again and added to splenocytes obtained from immunized
C57BL/6 mice and stimulated with the specific peptide as described
above. Pretreatment of Gr-1+ cells with
anti-H2Db, but not with
H2Dd Ab completely abrogated the inhibitory
effect of these cells on T cells (Fig. 5D). These data
indicate that MHC class I molecules are closely involved in
Gr-1+ cell-mediated T cell inhibition. Differentiation of Gr-1+ cells abrogates negative effect on T cell response
Next we investigated whether differentiation of
Gr-1+ cells might eliminate their inhibition of T
cells. Gr-1+ cell were isolated from spleens of
tumor-bearing mice and cultured for 5–6 days in complete medium. Less
than 10% viable cells were found after that time. This supports the
hypothesis that those
Gr-1+CD11b+ cells were in
fact immature myeloid cells incapable of surviving without growth
factors. Different concentrations of GM-CSF were used to support cell
viability and differentiation. In addition to GM-CSF we used IL-4 and
ATRA. IL-4 is known to selectively inhibit macrophage differentiation
and to promote differentiation of the dendritic cells. ATRA is a
natural oxidative metabolite of vitamin A and is known to be a
regulator of cell differentiation (21, 22). ATRA induces
terminal differentiation of promyelocytes into mature neutrophils in
patients with M3 (acute promyelocytic) leukemia (23).
Recently, we have shown that ATRA induced differentiation of immature
myeloid cells isolated from cancer patients (8). Because
Gr-1+ cells were represented by immature myeloid
cells on early stages of differentiation we hypothesized that these
cells can be differentiated into mature cells by ATRA. Five- to 6-day
incubation of Gr-1+ cells with GM-CSF at optimal
concentration (20 ng/ml) provided >90% cell viability. The total
number of viable cells remained the same as was used at the start of
the culture. Combination of GM-CSF with 10 ng/ml IL-4 or with 1 µM
ATRA showed similar results. Phenotypic analysis of these cells by flow
cytometry revealed that all cells retained CD11b and MHC class I
expression. More than half of the cells lost Gr-1 expression after
incubation with GM-CSF alone and >80% after incubation with GM-CSF
and IL-4. A combination of GM-CSF and ATRA decreased the presence of
Gr-1+ cells even further (Fig. 6A). The proportion of the
cells with surface expression of MHC class II increased >2-fold
compared with freshly isolated Gr-1+ cells.
Almost 10% of the cells treated with GM-CSF or GM-CSF and IL-4, but
not with ATRA, expressed both MHC class II and B7-2 (Fig. 6A). No such cells were detected among freshly isolated
Gr-1+ cells (data not shown). To investigate
whether these cultured cells retained their ability to inhibit
peptide-specific T cell response, splenocytes from immunized mice were
stimulated with peptides in the presence of freshly isolated
Gr-1+ cells or Gr-1+ cells
cultured for 5–6 days with GM-CSF alone or with a combination of
GM-CSF and IL-4 or ATRA. Freshly isolated Gr-1+
cells decreased the number of peptide-specific IFN--producing cells
>5-fold (Fig. 6B). This inhibitory potential was completely
lost after a 5- to 6-day culture with all tested substances.
Control levels of IFN--producing cells were seen in the presence of
as much as 10% of these cells (Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several groups have previously reported increased accumulation of immature myeloid cells and Mac-1+ (CD11b) macrophages in tumor-bearing hosts (2, 5, 6, 24). More recently, increased production of a more defined population of Gr-1+CD11b+ immature myeloid cells has been described in several mouse tumor models (10, 11). In this study we have also observed a 5- to 10-fold increase in the presence of these cells in two different tumor models. Thus it appears that increased production of immature myeloid cells in cancer is a widespread phenomenon. Increased production of these cells might be triggered by different soluble tumor-derived factors. Treatment of mice with one of these factors, vascular endothelial growth factor (VEGF), resulted in dramatic accumulation of Gr-1+ cells in peripheral lymphoid organs (25). These cells may play an important role in the inability of the immune system to recognize and eliminate tumor cells.
In this study we sought to clarify the effect of these cells on
specific T cell functions. Previous studies have demonstrated that
macrophages and myeloid cell-enriched population of splenocytes from
tumor-bearing mice inhibited T cell proliferation in response to CD3
ligation or various mitogens (4, 11, 26). To our surprise,
in both tested models Gr-1+ cells isolated by
cell sorting from tumor-bearing mice did not affect Con A-inducible
proliferation or IL-2 production by T cells isolated from syngeneic
control animals. To test the effect of Gr-1+
cells on T cell proliferation induced via TCR complex we used
Ag-specific T cells from transgenic mice. These cells have TCR
specific for HA peptide presented by MHC class II. Stimulation of these
T cells with the specific peptide resulted in strong proliferative
response and IL-2 production, and Gr-1+ myeloid
cells did not affect T cell response to this peptide. Thus,
Gr-1+ cells did not impair CD4-mediated T cell
response. These data are somewhat in contrast to previously published
observations (9, 11). It can be explained by the fact that
in this study we used highly purified Gr-1+
cells. In all previous studies enriched populations of APCs,
macrophages, or myeloid cells were used. It is likely that the presence
of mature or immature macrophages in those cell fractions may
dramatically affect the result of the experiments. Mature and immature
macrophages are known to produce a variety of different factors that
nonspecifically inhibit T cell function. Indeed, blockade of TGF-
and inhibition of NO production by these cells completely abrogated the
observed inhibitory effect of myeloid cells in previous studies
(11, 26).
We have investigated whether the same number of
Gr-1+ cells might affect CD8-mediated T cell
response. Two models with defined MHC class I restricted peptides were
used. These peptides are presented by MHC class I and specifically
activate CD8+ CTL (14, 16, 27). To
test T cell responses we measured peptide-specific IFN- production
by T cells in an ELISPOT assay. Specific peptides induced a 3- to
5-fold increase in the number of IFN--producing cells in immunized
mice. In seven independently performed experiments using two different
experimental models, Gr-1+ cells at a ratio as
low as 1:20 almost completely abrogated this increase. This suggests
that the presence of small numbers of Gr-1+
myeloid cells may be sufficient to inhibit a CD8-mediated T cell
response. These findings were confirmed by in vivo experiments. T cells
from mice treated with specific peptide-loaded
Gr-1+ cells lost their ability to respond to this
peptide although they reacted normally to stimulation with Con A. This
supports the hypothesis that relatively small numbers of
Gr-1+ cells induce Ag-specific, but not a general
immune suppression.
What could be a mechanism of this inhibition? It appears that direct cell-to-cell contact is required for Gr-1+ cell-mediated inhibition of T cell response, because conditioned medium from Gr-1+ cells did not affect T cell response to the peptide. Experiments with semi-permeable membranes confirmed these conclusions. Our data suggest that NO may be involved in described Gr-1+ cell-mediated effects. It appears that the role of NO increases with increased number of Gr-1+ cells. If high concentration of Gr-1+ cells is used (as was done in previous studies), NO production plays a critical role in nonspecific T cell inhibition by Gr-1+ cells. If a relatively low proportion of Gr-1+ cells is used (2.5–10%), the NO role is not so prominent, although still important. It is possible that NO production by Gr-1+ cells is increased after their contact with other cells. The mechanism of NO involvement is under investigation at this time.
However, these data could not explain a dichotomy in Gr-1+ cell effects on CD4- and CD8-mediated T cell responses. The explanation may lie in the phenotype of these cells. In contrast to Gr-1+ cells present in control mice, Gr-1+ cells from tumor-bearing animals expressed little or no MHC class II molecules, whereas they retained relatively high level MHC class I molecules. We hypothesized that these cells were unable to present Ags via MHC class II and, therefore, could not affect CD4-mediated T cell response. Conversely, immature Gr-1+ myeloid cells were able to present Ags in the context of MHC class I. Therefore, these cells can specifically block MHC class I-restricted T cell response. To test this hypothesis we blocked MHC class I expression on the surface of Gr-1+ cells using mAb and then tested their ability to inhibit T cell response to the specific peptide. MAb against MHC class I completely abrogated Gr-1+ cell-mediated inhibition of T cell response to the peptide. This indicates that observed inhibition is mediated by MHC class I presentation of the Ag. The exact mechanism of this inhibition is under investigation at this time.
We also investigated whether differentiation of Gr-1+ cells may decrease or eliminate their inhibitory potential. A previous study has suggested that differentiation of immature cells may reduce their inhibitory activity (5). In this study we have shown that Gr-1+ cells were not able to survive 5- to 6-day culture without presence of growth factors. This supports the hypothesis that these cells are not a subset of macrophages, but truly immature myeloid cells. In vitro culture of Gr-1+ cells with GM-CSF alone or with GM-CSF and IL-4 down-regulated Gr-1+ expression and increased the proportion of cells expressing MHC class II molecules. These cells did not block a peptide-specific T cell response. A naturally occurring isomer of retinoic acid, ATRA is a well-known factor capable of induction of differentiation of human leukemia cell line HL-60 and freshly isolated acute promyelocytic leukemia cells (28, 29). ATRA may also affect the growth of normal hemopoietic progenitors and blast progenitors in acute myelogeneous leukemia. However, these effects of ATRA depend on culture conditions (30, 31, 32). Because of the nature of Gr-1+CD11b+ immature myeloid cells we investigated whether addition of ATRA may help in the differentiation of these cells. Addition of ATRA to GM-CSF dramatically reduced expression of Gr-1+ on cell surface, but did not significantly affect expression of MHC class II or B7-2. However, these cells also did not inhibit peptide-specific T cell response. Currently we are investigating possible mechanisms of these effects.
Our data indicate that the presence of small numbers of immature myeloid cells may inhibit Ag-specific CD8-mediated T cell response. Advanced stage cancer is associated with increased accumulation of immature myeloid cells, which are able to block Ag-specific T cell responses (7, 8). This may provide one of the possible explanations of the difficulties in achieving a clear therapeutic effect of tumor vaccines in some preclinical and clinical studies dealing with advanced disease. Our study demonstrates a necessity of a combination of vaccination with a treatment able to eliminate immature myeloid cells. Differentiation of these cells may be one of the approaches. It is possible that positive effects of GM-CSF-producing tumor vaccines (33, 34) may be associated with reduction of immature myeloid cells and elimination of negative signal delivered by these cells. ATRA may be another potential adjuvant for vaccination of patients with advanced stage cancer.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dmitry Gabrilovich, H. Lee Moffitt Cancer Center, University of South Florida, MRC-2E, Room 2067, 12902 Magnolia Drive, Tampa, FL 33612.
3 Abbreviations used in this paper: HA, hemagglutinin; HPV, human papillomavirus; ATRA, all-trans retinoic acid; ELISPOT, enzyme-linked immunospot; LMMA, NG-monomethyl-L-arginine.
Received for publication November 1, 2000. Accepted for publication February 21, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 D. Ilkovitch and D. M. Lopez Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec Blood, May 7, 2009; 113(19): 4729 - 4739. [Abstract] [Full Text] [PDF]
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J. S. Pufnock and J. L. Rothstein Oncoprotein Signaling Mediates Tumor-Specific Inflammation and Enhances Tumor Progression J. Immunol., May 1, 2009; 182(9): 5498 - 5506. [Abstract] [Full Text] [PDF]
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S. Ostrand-Rosenberg and P. Sinha Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer J. Immunol., April 15, 2009; 182(8): 4499 - 4506. [Abstract] [Full Text] [PDF]
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J. S. Ko, A. H. Zea, B. I. Rini, J. L. Ireland, P. Elson, P. Cohen, A. Golshayan, P. A. Rayman, L. Wood, J. Garcia, et al. Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients Clin. Cancer Res., March 15, 2009; 15(6): 2148 - 2157. [Abstract] [Full Text] [PDF]
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 P. A. Nigrovic, D. H.D. Gray, T. Jones, J. Hallgren, F. C. Kuo, B. Chaletzky, M. Gurish, D. Mathis, C. Benoist, and D. M. Lee Genetic Inversion in Mast Cell-Deficient Wsh Mice Interrupts Corin and Manifests as Hematopoietic and Cardiac Aberrancy Am. J. Pathol., December 1, 2008; 173(6): 1693 - 1701. [Abstract] [Full Text] [PDF]
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N. Nausch, I. E. Galani, E. Schlecker, and A. Cerwenka Mononuclear myeloid-derived "suppressor" cells express RAE-1 and activate natural killer cells Blood, November 15, 2008; 112(10): 4080 - 4089. [Abstract] [Full Text] [PDF]
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J.-I. Youn, S. Nagaraj, M. Collazo, and D. I. Gabrilovich Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice J. Immunol., October 15, 2008; 181(8): 5791 - 5802. [Abstract] [Full Text] [PDF]
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 P. Cheng, C. A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M. M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein J. Exp. Med., September 29, 2008; 205(10): 2235 - 2249. [Abstract] [Full Text] [PDF]
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S. Watanabe, K. Deguchi, R. Zheng, H. Tamai, L.-x. Wang, P. A. Cohen, and S. Shu Tumor-Induced CD11b+Gr-1+ Myeloid Cells Suppress T Cell Sensitization in Tumor-Draining Lymph Nodes J. Immunol., September 1, 2008; 181(5): 3291 - 3300. [Abstract] [Full Text] [PDF]
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G. Willimsky, M. Czeh, C. Loddenkemper, J. Gellermann, K. Schmidt, P. Wust, H. Stein, and T. Blankenstein Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness J. Exp. Med., July 7, 2008; 205(7): 1687 - 1700. [Abstract] [Full Text] [PDF]
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K. Movahedi, M. Guilliams, J. Van den Bossche, R. Van den Bergh, C. Gysemans, A. Beschin, P. De Baetselier, and J. A. Van Ginderachter Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity Blood, April 15, 2008; 111(8): 4233 - 4244. [Abstract] [Full Text] [PDF]
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J. Tschop, A. Martignoni, H. S. Goetzman, L. G. Choi, Q. Wang, J. G. Noel, C. K. Ogle, T. A. Pritts, J. A. Johannigman, A. B. Lentsch, et al. {gamma}{delta} T cells mitigate the organ injury and mortality of sepsis J. Leukoc. Biol., March 1, 2008; 83(3): 581 - 588. [Abstract] [Full Text] [PDF]
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I. Vaknin, L. Blinder, L. Wang, R. Gazit, E. Shapira, O. Genina, M. Pines, E. Pikarsky, and M. Baniyash A common pathway mediated through Toll-like receptors leads to T- and natural killer-cell immunosuppression Blood, February 1, 2008; 111(3): 1437 - 1447. [Abstract] [Full Text] [PDF]
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C. Melani, S. Sangaletti, F. M. Barazzetta, Z. Werb, and M. P. Colombo Amino-Biphosphonate Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma Cancer Res., December 1, 2007; 67(23): 11438 - 11446. [Abstract] [Full Text] [PDF]
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Y. Nefedova, M. Fishman, S. Sherman, X. Wang, A. A. Beg, and D. I. Gabrilovich Mechanism of All-Trans Retinoic Acid Effect on Tumor-Associated Myeloid-Derived Suppressor Cells Cancer Res., November 15, 2007; 67(22): 11021 - 11028. [Abstract] [Full Text] [PDF]
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P. C. Kousis, B. W. Henderson, P. G. Maier, and S. O. Gollnick Photodynamic Therapy Enhancement of Antitumor Immunity Is Regulated by Neutrophils Cancer Res., November 1, 2007; 67(21): 10501 - 10510. [Abstract] [Full Text] [PDF]
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S. K. Bunt, L. Yang, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression Cancer Res., October 15, 2007; 67(20): 10019 - 10026. [Abstract] [Full Text] [PDF]
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B. Zhu, Y. Bando, S. Xiao, K. Yang, A. C. Anderson, V. K. Kuchroo, and S. J. Khoury CD11b+Ly-6Chi Suppressive Monocytes in Experimental Autoimmune Encephalomyelitis J. Immunol., October 15, 2007; 179(8): 5228 - 5237. [Abstract] [Full Text] [PDF]
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C. E. Clark, S. R. Hingorani, R. Mick, C. Combs, D. A. Tuveson, and R. H. Vonderheide Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion Cancer Res., October 1, 2007; 67(19): 9518 - 9527. [Abstract] [Full Text] [PDF]
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H.-J. Ko, Y.-J. Kim, Y.-S. Kim, W.-S. Chang, S.-Y. Ko, S.-Y. Chang, S. Sakaguchi, and C.-Y. Kang A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model Cancer Res., August 1, 2007; 67(15): 7477 - 7486. [Abstract] [Full Text] [PDF]
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M. J. Delano, P. O. Scumpia, J. S. Weinstein, D. Coco, S. Nagaraj, K. M. Kelly-Scumpia, K. A. O'Malley, J. L. Wynn, S. Antonenko, S. Z. Al-Quran, et al. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis J. Exp. Med., June 11, 2007; 204(6): 1463 - 1474. [Abstract] [Full Text] [PDF]
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P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells Cancer Res., May 1, 2007; 67(9): 4507 - 4513. [Abstract] [Full Text] [PDF]
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S. K. Watkins, N. K. Egilmez, J. Suttles, and R. D. Stout IL-12 Rapidly Alters the Functional Profile of Tumor-Associated and Tumor-Infiltrating Macrophages In Vitro and In Vivo J. Immunol., February 1, 2007; 178(3): 1357 - 1362. [Abstract] [Full Text] [PDF]
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R. Yang and R. B.S. Roden The Terminology Issue for Myeloid-Derived Suppressor Cells Cancer Res., January 1, 2007; 67(1): 426 - 426. [Full Text] [PDF]
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 J. W. Rasmussen, J. Cello, H. Gil, C. A. Forestal, M. B. Furie, D. G. Thanassi, and J. L. Benach Mac-1+ Cells Are the Predominant Subset in the Early Hepatic Lesions of Mice Infected with Francisella tularensis Infect. Immun., December 1, 2006; 74(12): 6590 - 6598. [Abstract] [Full Text] [PDF]
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K. Yanagisawa, M. A. Exley, X. Jiang, N. Ohkochi, M. Taniguchi, and K.-i. Seino Hyporesponsiveness to Natural Killer T-Cell Ligand {alpha}-Galactosylceramide in Cancer-Bearing State Mediated by CD11b+ Gr-1+ Cells Producing Nitric Oxide Cancer Res., December 1, 2006; 66(23): 11441 - 11446. [Abstract] [Full Text] [PDF]
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M. J. Dobrzanski, J. B. Reome, J. C. Hylind, and K. A. Rewers-Felkins CD8-Mediated Type 1 Antitumor Responses Selectively Modulate Endogenous Differentiated and Nondifferentiated T Cell Localization, Activation, and Function in Progressive Breast Cancer J. Immunol., December 1, 2006; 177(11): 8191 - 8201. [Abstract] [Full Text] [PDF]
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A. V. Ezernitchi, I. Vaknin, L. Cohen-Daniel, O. Levy, E. Manaster, A. Halabi, E. Pikarsky, L. Shapira, and M. Baniyash TCR {zeta} Down-Regulation under Chronic Inflammation Is Mediated by Myeloid Suppressor Cells Differentially Distributed between Various Lymphatic Organs J. Immunol., October 1, 2006; 177(7): 4763 - 4772. [Abstract] [Full Text] [PDF]
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N. Mirza, M. Fishman, I. Fricke, M. Dunn, A. M. Neuger, T. J. Frost, R. M. Lush, S. Antonia, and D. I. Gabrilovich All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer Patients. Cancer Res., September 15, 2006; 66(18): 9299 - 9307. [Abstract] [Full Text] [PDF]
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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms. Clin. Cancer Res., August 15, 2006; 12(16): 4794 - 4803. [Abstract] [Full Text] [PDF]
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K. C. McKenna and J. A. Kapp Accumulation of Immunosuppressive CD11b+ Myeloid Cells Correlates with the Failure to Prevent Tumor Growth in the Anterior Chamber of the Eye J. Immunol., August 1, 2006; 177(3): 1599 - 1608. [Abstract] [Full Text] [PDF]
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J. A. Van Ginderachter, S. Meerschaut, Y. Liu, L. Brys, K. De Groeve, G. Hassanzadeh Ghassabeh, G. Raes, and P. De Baetselier Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer Blood, July 15, 2006; 108(2): 525 - 535. [Abstract] [Full Text] [PDF]
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R. Yang, Z. Cai, Y. Zhang, W. H. Yutzy IV, K. F. Roby, and R. B.S. Roden CD80 in Immune Suppression by Mouse Ovarian Carcinoma-Associated Gr-1+CD11b+ Myeloid Cells. Cancer Res., July 1, 2006; 66(13): 6807 - 6815. [Abstract] [Full Text] [PDF]
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R. Kim, M. Emi, K. Tanabe, and K. Arihiro Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression Cancer Res., June 1, 2006; 66(11): 5527 - 5536. [Abstract] [Full Text] [PDF]
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A. B. Frey and N. Monu Effector-phase tolerance: another mechanism of how cancer escapes antitumor immune response J. Leukoc. Biol., April 1, 2006; 79(4): 652 - 662. [Abstract] [Full Text] [PDF]
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Z. F. M. Vasconcelos, B. M. dos Santos, J. Farache, T. S. S. Palmeira, R. B. Areal, J. M. T. Cunha, M. A. Barcinski, and A. Bonomo G-CSF-treated granulocytes inhibit acute graft-versus-host disease Blood, March 1, 2006; 107(5): 2192 - 2199. [Abstract] [Full Text] [PDF]
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V. P. Makarenkova, V. Bansal, B. M. Matta, L. A. Perez, and J. B. Ochoa CD11b+/Gr-1+ Myeloid Suppressor Cells Cause T Cell Dysfunction after Traumatic Stress J. Immunol., February 15, 2006; 176(4): 2085 - 2094. [Abstract] [Full Text] [PDF]
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B. Huang, P.-Y. Pan, Q. Li, A. I. Sato, D. E. Levy, J. Bromberg, C. M. Divino, and S.-H. Chen Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host Cancer Res., January 15, 2006; 66(2): 1123 - 1131. [Abstract] [Full Text] [PDF]
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S. K. Bunt, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression J. Immunol., January 1, 2006; 176(1): 284 - 290. [Abstract] [Full Text] [PDF]
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P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Interleukin-13-regulated M2 Macrophages in Combination with Myeloid Suppressor Cells Block Immune Surveillance against Metastasis Cancer Res., December 15, 2005; 65(24): 11743 - 11751. [Abstract] [Full Text] [PDF]
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M. Torroella-Kouri, X. Ma, G. Perry, M. Ivanova, P. J. Cejas, J. L. Owen, V. Iragavarapu-Charyulu, and D. M. Lopez Diminished Expression of Transcription Factors Nuclear Factor {kappa}B and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor-Bearing Mice Cancer Res., November 15, 2005; 65(22): 10578 - 10584. [Abstract] [Full Text] [PDF]
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P. C. Rodriguez, C. P. Hernandez, D. Quiceno, S. M. Dubinett, J. Zabaleta, J. B. Ochoa, J. Gilbert, and A. C. Ochoa Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. Exp. Med., October 3, 2005; 202(7): 931 - 939. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, S. Nagaraj, and D. I. Gabrilovich Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells J. Immunol., October 1, 2005; 175(7): 4583 - 4592. [Abstract] [Full Text] [PDF]
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E. Suzuki, V. Kapoor, A. S. Jassar, L. R. Kaiser, and S. M. Albelda Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity Clin. Cancer Res., September 15, 2005; 11(18): 6713 - 6721. [Abstract] [Full Text] [PDF]
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L. Brys, A. Beschin, G. Raes, G. H. Ghassabeh, W. Noel, J. Brandt, F. Brombacher, and P. D. Baetselier Reactive Oxygen Species and 12/15-Lipoxygenase Contribute to the Antiproliferative Capacity of Alternatively Activated Myeloid Cells Elicited during Helminth Infection J. Immunol., May 15, 2005; 174(10): 6095 - 6104. [Abstract] [Full Text] [PDF]
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S. Kusmartsev and D. I. Gabrilovich STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion J. Immunol., April 15, 2005; 174(8): 4880 - 4891. [Abstract] [Full Text] [PDF]
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P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease J. Immunol., January 15, 2005; 174(2): 636 - 645. [Abstract] [Full Text] [PDF]
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M. M. Dikov, J. E. Ohm, N. Ray, E. E. Tchekneva, J. Burlison, D. Moghanaki, S. Nadaf, and D. P. Carbone Differential Roles of Vascular Endothelial Growth Factor Receptors 1 and 2 in Dendritic Cell Differentiation J. Immunol., January 1, 2005; 174(1): 215 - 222. [Abstract] [Full Text] [PDF]
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 V. Bansal, K. M. Syres, V. Makarenkova, R. Brannon, B. Matta, B. G. Harbrecht, and J. B. Ochoa Interactions Between Fatty Acids and Arginine Metabolism: Implications for the Design of Immune-Enhancing Diets JPEN J Parenter Enteral Nutr, January 1, 2005; 29(1_suppl): S75 - S80. [Abstract] [Full Text] [PDF]
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T. Ghansah, K. H. T. Paraiso, S. Highfill, C. Desponts, S. May, J. K. McIntosh, J.-W. Wang, J. Ninos, J. Brayer, F. Cheng, et al. Expansion of Myeloid Suppressor Cells in SHIP-Deficient Mice Represses Allogeneic T Cell Responses J. Immunol., December 15, 2004; 173(12): 7324 - 7330. [Abstract] [Full Text] [PDF]
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 L. M. Hengesbach and K. A. Hoag Physiological Concentrations of Retinoic Acid Favor Myeloid Dendritic Cell Development over Granulocyte Development in Cultures of Bone Marrow Cells from Mice J. Nutr., October 1, 2004; 134(10): 2653 - 2659. [Abstract] [Full Text] [PDF]
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P. Serafini, R. Carbley, K. A. Noonan, G. Tan, V. Bronte, and I. Borrello High-Dose Granulocyte-Macrophage Colony-Stimulating Factor-Producing Vaccines Impair the Immune Response through the Recruitment of Myeloid Suppressor Cells Cancer Res., September 1, 2004; 64(17): 6337 - 6343. [Abstract] [Full Text] [PDF]
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P. C. Rodriguez, D. G. Quiceno, J. Zabaleta, B. Ortiz, A. H. Zea, M. B. Piazuelo, A. Delgado, P. Correa, J. Brayer, E. M. Sotomayor, et al. Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses Cancer Res., August 15, 2004; 64(16): 5839 - 5849. [Abstract] [Full Text] [PDF]
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Q. Li, P.-Y. Pan, P. Gu, D. Xu, and S.-H. Chen Role of Immature Myeloid Gr-1+ Cells in the Development of Antitumor Immunity Cancer Res., February 1, 2004; 64(3): 1130 - 1139. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, Y. Nefedova, D. Yoder, and D. I. Gabrilovich Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species J. Immunol., January 15, 2004; 172(2): 989 - 999. [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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D. G. Mordue and L. D. Sibley A novel population of Gr-1+-activated macrophages induced during acute toxoplasmosis J. Leukoc. Biol., December 1, 2003; 74(6): 1015 - 1025. [Abstract] [Full Text]
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C. Melani, C. Chiodoni, G. Forni, and M. P. Colombo Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity Blood, September 15, 2003; 102(6): 2138 - 2145. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, F. Cheng, B. Yu, Y. Nefedova, E. Sotomayor, R. Lush, and D. Gabrilovich All-trans-Retinoic Acid Eliminates Immature Myeloid Cells from Tumor-bearing Mice and Improves the Effect of Vaccination Cancer Res., August 1, 2003; 63(15): 4441 - 4449. [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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Y. Liu, J. A. Van Ginderachter, L. Brys, P. De Baetselier, G. Raes, and A. B. Geldhof Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells J. Immunol., May 15, 2003; 170(10): 5064 - 5074. [Abstract] [Full Text] [PDF]
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B. Yu, S. Kusmartsev, F. Cheng, M. Paolini, Y. Nefedova, E. Sotomayor, and D. Gabrilovich Effective Combination of Chemotherapy and Dendritic Cell Administration for the Treatment of Advanced-Stage Experimental Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 285 - 294. [Abstract] [Full Text] [PDF]
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V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
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A. B. Geldhof, J. A. Van Ginderachter, Y. Liu, W. Noel, G. Raes, and P. De Baetselier Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation Blood, December 1, 2002; 100(12): 4049 - 4058. [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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L. I. Terrazas, K. L. Walsh, D. Piskorska, E. McGuire, and D. A. Harn Jr. The Schistosome Oligosaccharide Lacto-N-neotetraose Expands Gr1+ Cells That Secrete Anti-inflammatory Cytokines and Inhibit Proliferation of Naive CD4+ Cells: A Potential Mechanism for Immune Polarization in Helminth Infections J. Immunol., November 1, 2001; 167(9): 5294 - 5303. [Abstract] [Full Text] [PDF]
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