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Clinical Trials |
Department of Medicine and The Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232 [B. A., J. R. R., B. L., S. N., D. P. C.], and Departments of Pathology [D. I. G.], Urology [E. D. K.], and Medicine [J. I. C.] and Cardinal Bernardin Cancer Center [D. I. G., E. D. K., J. I. C.], Loyola University Medical Center, Maywood, Illinois 60153
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Fourteen healthy volunteers served as
controls for the PB DC study. LNs were obtained during tumor resection
in HNSCC patients, and only that part of the LNs not needed for medical
decision-making was used for the isolation of DCs. Control tonsil
tissues were obtained from nine age-matched individuals undergoing
tonsillectomy for sleep apnea indications without a history or recent
evidence of infection. The three patients shown in Table 4
were treated
on a three-arm randomized trial of chemotherapy with carboplatin and
Taxol in combination with humanized anti-VEGF antibody (Genentech, VCC
THO9806). After chemotherapy, all three patients studied received the
antibody alone at either 15 or 7.5 mg/kg every 3 weeks for at least 3
months before the blood was assessed. Informed consent was obtained
from all individuals.
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Cell Isolation from PB.
DCs and T cells were isolated from PB as described (14)
with some modifications. Briefly, mononuclear cells obtained after
centrifugation of PB over a Ficoll-paque gradient were incubated with
2-aminoethylisothiouronium bromide (Sigma)-treated sheep RBCs (R).
Cells that adhered to the red cells (R+) and those that did not (R–)
were separated on a Ficoll-paque gradient. R– cells were then
incubated for 24–36 h in CCM. Nonadherent cells were centrifuged over
a metrizamide gradient (7.25 g of metrizamide in 50 ml of CCM) to
obtain an enriched fraction of DCs. For all functional tests,
DCs were further enriched using a magnetic bead separation technique.
Briefly, the DC fraction isolated as described above was treated at
4°C with a mixture of monoclonal antibodies: anti-CD3, anti-CD14,
anti-CD19, and anti-CD57/HNK. After a 30-min incubation, cells were
washed and labeled with goat antimouse IgG antibody conjugated with
magnetic beads (Dynal), followed by magnetic separation. In control
individuals, the resulting cell population contained more than 95%
DCs, as estimated by flow cytometry.
R+ cells were further processed to obtain an enriched T cell fraction by osmotic lysis of the red cells followed by overnight incubation in CCM at 37°C. More than 90% of nonadherent cells were T cells, as estimated by flow cytometry.
Cell Isolation from LNs.
For head and neck cancer patients, one-third to one-half of uninvolved
cervical LNs were obtained at the time of planned surgery. For
controls, one-quarter to one-half of tonsillectomy specimens were
obtained at the time of surgery. Specimens were cleaned of adipose and
connective tissue, finely minced, and incubated in 400 units/ml of
collagenase for 30 min. Cells were then passed through a 70
µM cell strainer and washed in PBS before being placed
over Ficoll-paque. The remainder of the DC isolation was the same as
for PB DCs described above.
MLR and Antigen-specific T-cell Proliferation.
The ability of DCs to stimulate allogeneic T cells was tested in MLR.
Because the strength of the response in allogeneic MLR depends on
mismatch in HLA, occasionally, a low level of proliferaion was detected
even in response to the donor’s DCs. Although these low values did not
change the overall results, they significantly increased a variation of
the data and complicated the analysis. To minimize the effect of
differences in HLA between individuals on allogeneic T cell
proliferation, DCs from each patient and control individual were tested
against allogeneic T cells from three control individuals, and only
maximal values of responses were used. Fifty thousand T cells were
plated in each well of 96-well round-bottomed plates, and DCs and T
cells were cultured at ratios of 1:20, 1:40, 1:80, and 1:160 for 5
days. One µCi of [3H]thymidine was added to
each well 18 h prior to harvesting the cells.
[3H]Thymidine uptake was counted in a liquid
scintillation counter (Beckman, Palo Alto, CA).
Antigen-specific T cell response was measured using TT. DCs were cultured with autologous T cells in the presence of 1.0 µg/ml TT. [3H]Thymidine was added after 4 days of culture, and uptake was counted 18 h later in a liquid scintillation counter. Background levels of T cell proliferation (with no TT) were subtracted.
Flow Cytometry.
Cells were labeled with PE-, FITC-, or Quantum Red-conjugated
antibodies by incubation on ice for 30 min followed by washing with
PBS. Data acquisition and analysis were performed on a FACSCalibur flow
cytometer (Becton Dickson, Mountain View, CA) using Cell Quest
software.
Assay for the Presence of Growth Factor and Cytokines in PB.
Patient and control plasma samples were obtained by centrifugation of
PB at 500 x g for 10 min. To minimize nonspecific
binding to lipids, all samples were obtained after 3–4 h of fasting
and spun down at 10,000 x g for 30 min prior to
testing. Plasma samples were stored at –20°C. Concentrations of
VEGF, TGF-ß1, IL-6, IL-10, GM-CSF, and M-CSF were measured using
ELISA kits (R&D Systems) and assayed on a spectrophotometer. Data were
analyzed using DeltaSoft software.
Statistical Analysis.
Statistical analysis was performed using parametric and nonparametric
methods and JMP statistical software (SAS Institute Inc., Cary,
NC).
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RESULTS |
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. This was consistent with previously
reported data from breast cancer patients (11)
. DC
activity in patients with advanced disease (stages 3–4) was
significantly lower than that in patients with early stages of cancer
(stages 1–2; P < 0.05). The activity of
patients’ LN DCs was also severely impaired (Fig. 1)
. No statistically
significant differences were seen between the activity of PB DCs and LN
DCs (Fig. 1)
. To exclude the possible effect of especially low values
on the average values of DC activity in the groups, we compared the
percentage of patients with decreased LN DC and PB DC functional
activity. As a control level in this case we used the level
corresponding to 1 SD below the median response of DCs from healthy
control individuals. The function of PB DCs was decreased in 12 of 18
patients (66.6%), and LN DC function was decreased in 14 of 18
patients (77.7%). There was no statistically significant difference
between PB and LN DC function. Thus, the function of PB DCs and
regional LN DCs appears to be equally affected in patients with HNSCC.
This suggests that DC defects in cancer patients are a systemic
phenomenon rather than a local effect of tumor-derived factors on
regional LN DCs.
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. Cancer patients had a
significantly lower percentage of these cells. Typical results are
shown in Fig. 2
. To calculate the proportion and absolute numbers of
DCs in control donors and cancer patients, DCs were enriched by
magnetic bead separation of freshly isolated mononuclear cells using
anti-CD3, CD14, CD19, and CD57 antibodies. Negatively selected enriched
populations of DCs were labeled with PE-conjugated lineage-specific
antibodies (anti-CD3, anti-CD14, anti-CD19, and anti-CD57
antibodies) and FITC-conjugated anti-HLA-DR antibody. Lineage-negative,
HLA-DR-positive cells were scored as DCs. Sixteen healthy volunteers
and 23 patients with HNSCC were studied. As shown in Table 2
, the proportion of DCs in PB was
significantly decreased in patients with stages 1–2 HNSCC. This
resulted in a 2-fold decrease in the total number of DCs. In patients
with advanced stages of HNSCC, the proportion of DCs was decreased even
further, with a 4-fold decrease in the total number of these cells
(Table 2)
. Thus, the number of DCs was dramatically reduced in the PB
of cancer patients, and the degree of reduction was associated with the
stage of disease.
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illustrates a typical profile in one of the control donors. More that
95% of Lin- cells also expressed HLA-DR and
thus can be classified as DCs. More than 80% of these cells expressed
the B7-2 molecule, and more than 60% expressed CD40, both of which are
markers of activated DCs. The proportion of these cells was
dramatically reduced in cancer patients because of the accumulation of
Lin- HLA-DR-,
B7-2-, or CD40- cells
(Fig. 3B)
. Thus, in vitro culture of cells
obtained from PB of cancer patients did not restore the presence of
DCs. This indicates that the observed decrease of DCs in PB from cancer
patients was not a transitory phenomenon. This decrease was associated
with marked increase in the presence of cells lacking markers of mature
cells. We refer to these marker-negative cells as "immature."
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and the presence of DCs in these fractions. Correlation was calculated
between an ability of DCs to stimulate allogeneic T cells obtained from
control individuals and the proportion of
Lin-HLA-DR+ or
Lin-B7-2+ cells. As
expected, the presence of Lin-
HLA-DR+ and Lin-
B7-2+ cells was closely correlated with
proliferation of allogeneic T cells in response to stimulation by DCs
(r = 0.72; P < 0.01).
To investigate the possible correlation between the presence of the
immature cells and clinical parameters, patients with three different
types of cancer were studied. Patients with each type of cancer were
divided into two groups: patients with advanced disease (stages 3–4)
and those with early stage disease (stages 1–2). In 11 healthy
volunteers, the proportions of cells were as follows:
Lin- HLA-DR-, 4.0 ±
1.2%; Lin- B7-2-,
15.0 ± 2.0%; Lin-
CD40-, 39.7 ± 5.0%. Patients with
breast cancer from both groups demonstrated a dramatic increase in the
proportion of immature cells. In patients with advanced disease, the
proportion of Lin-
HLA-DR- cells was increased almost 10-fold, and
Lin- B7-2- was increased
more than 4-fold as compared to control individuals (Fig. 4)
. The proportion of
Lin-HLA-DR- cells was
significantly higher in patients with advanced disease than in patients
with early stage disease (Fig. 4)
. An even more profound effect was
seen in patients with lung cancer. The proportion of
Lin- B7-2- cells was
increased almost six times, and Lin-
CD40- cells were increased more than 2-fold as
compared to controls (Fig. 4)
. As in the case of patients with breast
cancer, patients with advanced disease had a significantly higher
proportion of Lin-
HLA-DR- cells (Fig. 4)
. The proportion of
Lin- CD40- cells was
significantly higher than in controls only in patients with advanced
disease. The same trend was evident in the patients with HNSCC (Fig. 4)
. Thus, the proportion of immature cells was dramatically increased,
and this increase was closely associated with the stage of disease.
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, top panel).
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, bottom panel). We then asked whether the accumulation of immature cells was associated with the duration of the disease. Duration of the disease was calculated in weeks from the date of appearance of first symptoms of the disease and the date of blood collection. A statistically significant correlation between the presence of Lin- DR- cells and the duration of the disease was found for patients with breast cancer (r = +0.81, P = 0.014). However, no such correlation was seen for patients with HNSCC. Because of the relatively small numbers of patients with lung cancer, such an analysis was not performed in that group of patients. Thus, in all three types of cancer investigated here, the presence of immature cells was dramatically increased, and this increase was closely associated with the stage of disease, presence of tumor, and in some cases duration of disease.
Association of the Increased Proportion of Immature Cells with
Increased Concentrations of Growth Factors and Cytokines in the Plasma
of Cancer Patients.
Several factors have previously been implicated in defective DC
maturation in cancer (15
, 16
, 19)
. Here, we studied the
association between an elevated level of certain growth factors and
cytokines in the circulation and the observed increased proportion of
immature cells. Plasma samples were collected from 34 patients with
advanced cancer, and the levels of M-CSF, GM-CSF, VEGF, IL-6, IL-10 and
TGF-ß were determined by ELISA (R&D Systems). Control levels of these
cytokines were established using plasma from nine healthy volunteers.
For each growth factor and cytokine, two groups of patients were
compared: patients with the control levels of the factor (within 95%
confidence intervals of control samples) and patients with increased
levels of the factor. The proportion of immature cells was compared
between these two groups. It is important to note that no statistically
significant correlation between the levels of the factors was found
(data not shown). A significant proportion of patients demonstrated
increased concentrations of at least one of five factors (Table 3)
. We could not detect an increased
level of IL-10 in any of the studied patients. The proportion of
Lin- HLA DR- and
Lin- CD40- cells was
significantly lower in cancer patients with normal levels of VEGF in
plasma than in those with an elevated VEGF concentration (Table 3)
. The
same trend was evident in the presence of Lin-
B7-2- cells, but those differences did not reach
statistical significance. No such association with any other factor was
found (Table 3)
. Thus, these data suggest that VEGF might be involved
in the generation of immature cells in cancer patients as suggested by
animal and in vitro data.
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. It should be noted that none of these
patients had a significant tumor response, so the total amount of tumor
present at both evaluations was identical. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The Defect in DC Function in Cancer Patients Is Systemic Rather
Than Local.
Two main mechanisms might be responsible for the observed DC
deficiency. The first mechanism is that immature DCs may come in direct
contact with tumor cells, and this contact could affect their
maturation, including their ability to take up tumor antigen, migrate
to regional LNs, or present antigen to T cells. If any of these
mechanisms were prominent, one would expect more profound defects in
the numbers and function of DCs isolated from draining LNs than in DCs
isolated from PB. This might be especially evident in the earlier
stages of cancer. In a recent study, sentinel LNs in breast cancer
patients demonstrated a decreased density of paracortical DCs, a
reduced frequency of double positive S100 and MHC class II cells and a
predominance of immature DCs (20)
. Alternatively, tumors
may exert their effects via tumor-derived factors able to systemically
affect DC function or maturation in bone marrow and in other tissues.
This would be manifested by equal dysfunction of PB and LN DCs. In our
study of 18 patients with head and neck cancer, the function of both LN
and PB DCs was equally impaired. These data indicate that defects in
DCs is a systemic phenomenon rather than an effect confined to local
LNs.
The Appearance of Immature Cells Co-purified with DCs Is Clinically
and Functionally Relevant.
As was reported earlier, the presence of tumor-derived factors inhibits
DC differentiation from hematopoietic progenitors in vitro,
resulting in the generation of immature cells (13
, 15, 16, 17)
. Here, we asked whether this process takes place in
cancer patients and whether it results in a significant decrease in the
numbers of DCs. We used three markers closely associated with DCs:
HLA-DR, B7-2, and CD40. The two latter markers reflect the level of
functional maturation and activation of DCs. Using a combination of
purification and labeling techniques, we calculated the proportion and
absolute number of Lin-
HLA-DR+ DCs in the PB of patients with head and
neck cancer. Our results clearly demonstrate a significant decrease in
the proportion and number of DCs in patients with early stage cancer
and even more profound changes in patients with advanced disease. This
decrease was caused by the appearance of cells lacking typical markers
specific for the normal cell lineages. We have called them
immature cells. The proportion of these immature cells was the
same for patients with the three different types of cancer evaluated
here (breast, head and neck, and lung). In all three types of cancer,
this proportion increased with disease progression. The presence of
tumor was critical in the generation of immature cells, because the
proportion of these cells dropped dramatically 3–4 weeks after
surgery. This is consistent with the hypothesis that the generation of
these cells was caused by the production of soluble tumor-derived
factors. Thus, it appears that removal of the source of these factors
by surgical excision of the tumors restored the DC differentiation
process and resulted in improved numbers of DCs in the circulation 3–4
weeks later. We tried to establish a correlation between the presence
of immature cells and the duration of disease. A direct correlation was
found for patients with breast cancer, but the small number of patients
evaluated with lung cancer did not allow this analysis.
Patients with tumors of the oral cavity have a significantly higher rate of recurrence and a poorer prognosis than patients with similar stages of laryngeal cancer. The cause of these differences is not clear. It has been suggested that tumors of the oral cavity manifest later because of anatomical features of the site, and therefore, patients with oral cancer have a longer duration of the disease before diagnosis. We found a significantly higher proportion of immature cells for patients with oral cancer than in those with the same stage of laryngeal cancer. There was no difference in the duration of disease, age, or other factors between these two groups. These data suggest that there is a possibility that clinical differences between these two anatomical sites of otherwise similar tumors may be associated with immunological differences.
Taken together, these data suggest that the appearance of immature cells in the PB of cancer patients is closely associated with decreased presence of DCs and is clinically relevant. It is possible that tumor-derived factors might affect the normal process of DC differentiation, which results in the decreased presence of mature cells. Our data demonstrate that these immature cells were also functionally relevant. Elimination of these cells using fluorescence-activated cell sorting completely restored the functional potency of the DC fraction in vitro.5
Tumor-derived Factors Involved in Generation of Immature Cells.
At this time several factors have been implicated in defective DC
differentiation. Using neutralizing antibodies, we demonstrated
previously an important role for VEGF and possibly M-CSF in defective
DC differentiation (15)
. Continuous in vivo
VEGF infusions resulted in dramatic inhibition of DC production
(21)
. VEGF, which is produced by a majority of
tumors, plays an essential role in blood vessel formation, and an
elevated level of VEGF in the plasma of cancer patients is closely
associated with an adverse prognosis (22
, 23)
. It has been
recently reported that an elevated levels of VEGF in the vicinity of
tumors is closely associated with decreased tumor infiltration by DCs
in patients with gastric cancer (24)
. IL-10 is another
factor implicated in the defective DC function. IL-10 has been shown to
block the differentiation of monocytes into DCs (25)
and
to inhibit the function of epidermal Langerhans cells
(26, 27, 28)
and of monocyte- and
CD34+-derived DCs (19
, 29)
.
Two other factors, M-CSF and IL-6, have recently been reported to be
involved in defective DC differentiation. Neutralizing anti-IL-6 and
anti-M-CSF antibody abrogated the negative effect of supernatants from
renal cell carcinomas on DC differentiation, and incubation of
CD34+ progenitor cells with these factors shifted
cell differentiation from DCs to monocytes (16)
. It is
important to note that all these studies were performed in
vitro. To investigate the role of these and some other factors in
the generation of immature cells in cancer patients, we measured plasma
levels of six growth factors and cytokines, M-CSF, GM-CSF, IL-6, IL-10,
TGF-ß, and VEGF. Patients were divided into two groups, with normal
or elevated levels of each factor. The proportion of immature
cells was compared in these two groups. Only those patients with
elevated levels of VEGF showed statistically significantly increased
numbers of immature cells. Thus, these data support the hypothesis that
VEGF plays an important role in abnormal DC differentiation. This is
also supported by the data from patients treated with anti-VEGF
antibody. However, the proportion of immature cells for patients with
normal levels of VEGF was still higher than in controls, suggesting the
involvement of additional factors.
In conclusion, for the first time, we have demonstrated a dramatic decrease in the presence of mature DCs in the blood and regional LNs of cancer patients. This was caused by the accumulation of immature myeloid cells at different stages of differentiation. The presence of these cells correlated directly with the stage of the cancer and, in some cases, with its duration. Their presence also decreased after surgical removal of the tumor. The detailed study of the nature and the functional role of these cells is currently under way in our laboratories. Identification of the molecular pathways involved in these effects may lead to therapeutic approaches for blocking their production or inducing their differentiation in cancer patients. This would result in a significant improvement of the function of endogenous DCs and therefore possibly improve the efficacy of immunotherapy and the clinical outcome of the disease.
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FOOTNOTES |
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1 This work was supported by NIH Grant CA84488 (to
D. I. G.) and NIH Grant CA61242 (to D. P. C.). Part of this work
was presented at annual meeting of American Association for Cancer
Research, Philadelphia, PA, April 10–14, 1999. 
2 These authors equally contributed to this work.
3 To whom requests for reprints should be
addressed, at Cardinal Bernardin Cancer Center, Loyola University
Medical Center, Building 112, Room 203, Maywood, IL 60153. Phone:
(708) 327-3130; Fax: (708) 327-3238; E-mail dgabril@luc.edu.
4 The abbreviations used are: APC, antigen
presenting cell; CCM, complete culture medium; DC, dendritic cell;
GM-CSF, granulocyte macrophage colony-stimulating factor; HNSCC, head
and neck squamous cell carcinoma; LN, lymph node; M-CSF, macrophage
colony-stimulating factor; MLR, mixed leukocyte reaction; PB,
peripheral blood; PE, phycoerythrin; TT, tetanus toxoid; VEGF, vascular
endothelial growth factor.
Received 12/16/99; revised 2/10/00; accepted 2/10/00.
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