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,
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Division of Pulmonary and Critical Care Medicine and
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; and
West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA 90073
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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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B activation (16) as well as the
normal acquisition of APC molecules such as CD80, CD86, and HLA-DR.
Blocking and reconstitution studies suggest that tumor-secreted
vascular endothelial growth factor (VEGF), M-CSF, and IL-6 mediate
these effects (14, 15). In addition to CD34+ stem cells, CD14+ monocytes provide another source for generating functional DC (17, 18). We hypothesized that for tumor-induced suppression to be effective, factors present in the tumor environment must also interfere with the maturation and/or function of monocyte-derived DC. Human adherent PBMC were cultured with GM-CSF and IL-4 in the presence or absence of culture supernatants collected from a variety of tumor cell lines. In contrast to the responses reported for CD34+ precursors, DC generated from monocytes in the presence of TSN appeared mature, expressing essential cell surface molecules, enhanced translocation of RelB to the nucleus, and early development of T cell stimulatory activity. However, these cells did not develop full allostimulatory activity, had a diminished capacity to produce IL-12 and IL-10, and rapidly underwent apoptosis following this early, defective maturation process. While mediated by different mechanisms, TSN appears to effectively suppress the function of both monocyte- and stem cell-derived DC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The A549 non-small cell lung carcinoma, the IMR90 lung
fibroblast, the MCF-7 breast carcinoma (all from American Type Culture
Collection, Manassas, VA), the A427 lung adenocarcinoma (obtained from
Dr. J. A. Radosevich, Northwestern University, Chicago, IL), the
R11 renal cell carcinoma (generous gift of Dr. A. Belldegrun, UCLA
School of Medicine, Los Angeles, CA), and the UCLA-SOM-M14 (M14)
melanoma cell lines were maintained in complete medium composed of RPMI
1640 (Irvine Scientific, Santa Ana, CA) supplemented with 10%
heat-inactivated human AB serum (Gemini Bioproducts, Calabasas, CA),
penicillin-streptomycin-Fungizone (Life Technologies, Grand Island,
NY), and 10 mM HEPES (Sigma, St. Louis, MO). Cytokines used for DC
generation and stimulation included GM-CSF (sp. act., 1.13 x
107 U/mg; provided by Schering-Plough Research
Institute, Kenilworth, NJ), IL-4 (sp. act., 8 x
106 U/mg; R&D Systems, Minneapolis, MN), CD40L
(provided by Immunex, Seattle, WA), and IFN-
and IL-12 (Peprotech,
Rocky Hills, NJ). Abs used for phenotyping included fluorescently
conjugated anti-HLA-DR and anti-CD80 (Becton Dickinson, San
Jose), anti-CD14 and anti-CD40 (Caltag Laboratories,
Burlingame, CA), anti-CD83 (Serotec, Raleigh, NC), and
anti-CD11c and anti-CD86 (PharMingen, San Diego, CA). Abs used
to purify DC (anti-CD3, anti-CD19, anti-CD56) and T cells
(anti-CD14, anti-CD16, anti-CD19) were obtained from
PharMingen (no azide, low endotoxin). Neutralizing Abs were used at
5–10 µg/ml and included anti-IL-10, anti-VEGF,
anti-TGF-ß (all from R&D Systems), and
anti-PGE2 (generously provided by J.
Portanova, G. D. Searle, Skokie, IL).
Preparation of TSN and TSN-exposed DC
TSN were prepared by seeding 25-cm2 flasks with 1 x 106 tumor cells in 10 ml of complete medium. The culture supernatants were collected after 24 h, centrifuged to remove cells, and stored at -80°C. DC were generated from the adherent fraction of peripheral blood, as previously described (17, 19). Briefly, PBMC were allowed to adhere for 2 h in culture flasks, nonadherent cells were gently removed, and the remaining cells were cultured in complete medium supplemented with 800 U/ml (71 ng/ml) GM-CSF and 500 U/ml (63 ng/ml) IL-4. The effects of TSN on DC maturation were examined by replacing 0–50% of the culture medium with TSN at the initiation of culture. In some experiments, the TSN was washed out after 24 h and replaced with fresh medium and cytokines. In other experiments, IL-12 was added in addition to GM-CSF and IL-4. After either 4 or 7 days in culture, all free or loosely adherent cells were collected by vigorous rinsing. DC were further purified by negative depletion using an Ab mixture in conjunction with anti-mouse Ig-conjugated immunomagnetic beads (17) (Dynal, Lake Success, NY). To examine the effects of TSN on mature DC, control DC were collected on day 7 and cultured for 40 h in fresh medium and cytokines, in the presence or absence of 50% TSN.
DC phenotype and function
DC were analyzed by three-color FACS analysis using a FACScan II
flow cytometer and CellQuest software (Becton Dickinson) with
5,000–10,000 events acquired for each sample. Control and TSN-DC
collected on days 4 and 7 were assayed for their ability to stimulate
allogeneic T cells in an MLR. Purified DC were cocultured with 1
x 105 CD3+ T cells from an
unrelated donor at ratios of 1:20, 1:50, and 1:100 DC:T cells.
Allogeneic CD3+ T cells were prepared by negative
depletion of nonadherent PBMC with an Ab mixture and immunomagnetic
beads. The assays were performed in triplicate in round-bottom 96-well
plates. No TSN was present during the MLR assay. After 5 days of
coculture, the wells were pulsed for 18 h with 1 µCi/well
tritiated thymidine (Amersham, Arlington Heights, IL). Endocytosis was
assessed by uptake of FITC-dextran (20). DC were incubated
for 1 h at 37°C in the presence of 1 mg/ml FITC-dextran (40,000
m.w.; Molecular Probes, Eugene, OR). Control cells were incubated on
ice for 1 h. After extensive washing, the cells were analyzed by
single-color FACS analysis. Cytokine production was assessed by
stimulating purified DC (3 x 105 cells/ml)
for 24 h with CD40L (1 µg/ml) in the presence or absence of
IFN- (1000 U/ml) (21). DC supernatants were then
analyzed by ELISA for IL-12 p70 (Genzyme, Cambridge, MA),
PGE2 (Ab pairs; Cayman Chemical, Ann Arbor, MI),
and IL-10 (Ab pairs; PharMingen).
Western blot analysis of RelB
DC collected on days 4 and 7 were pelleted, washed, and lysed (4°C, 15 min; 10 mM HEPES, pH 7.9, 10 mM KCl, 1.5 mM MgCl2, 0.1 mM EDTA, 1 mM DTT, 0.5 mM PMSF, and 0.6% Nonidet P-40). After centrifugation (6000 rpm, 10 min), the supernatant (cytoplasmic protein) was collected. The pelleted nuclei were mixed with buffer (20 mM HEPES, pH 7.9, 0.4 M NaCl, 1.5 mM MgCl2, 0.1 mM EDTA, 0.1 mM EGTA, 0.5 mM DTT, 0.5 mM PMSF, 25% glycerol) and kept on ice with occasional vortex mixing. After centrifugation (13,000 rpm, 10 min), the supernatant (nuclear protein) was collected. For Western blotting, 20 µg protein samples were resolved on a 12% SDS-PAGE gel and transferred to Hybond-ECL membranes (Amersham Life Sciences, Arlington Heights, IL). The Western analysis was performed using anti-RelB and anti-actin (both from Santa Cruz Biotechnology, Santa Cruz, CA) and the Amersham Life Science enhanced chemiluminescence protocol.
Apoptosis
DC were assessed for apoptosis by two methods. The exposure of phosphatidylserine residues on the cell surface was measured using annexin-FITC, with dead cells identified with propidium iodide (Bender MedSytems kit, distributed by Biosource International, Camarillo, CA). These results were confirmed using a FACS-based TUNEL assay (APO-BrdU kit; PharMingen). For both of these assays, 10,000 events were collected on the FACScan II cytometer and analyzed with CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC phenotype and function
As shown in Fig. 1
, exposure of
maturing DC to TSN enhanced their early expression of cell surface
molecules associated in Ag presentation, including CD80 (B7-1), CD86
(B7-2), CD40, and HLA-DR. A marker expressed on both immature and
mature DC, CD11c, was reduced in cells cultured with TSN, while the
same cells expressed higher than control levels of CD83, a marker of
more mature DC. Between days 4 and 7, the expression of APC markers, as
measured by mean linear fluorescence intensity (LFI), was maintained
(CD80, 331 vs 313 LFI; CD83, 59 vs 63 LFI; CD11c, 5995 vs 5913 LFI) or
continued to increase (CD86, 2204 vs 3293 LFI; CD40, 494 vs 576 LFI;
HLA-DR, 3365 vs 4734 LFI) on control DC. In contrast, APC marker
expression remained relatively constant (CD86, 6637 vs 6108 LFI;
HLA-DR, 4752 vs 4990 LFI) or significantly decreased (CD80, 2137 vs
1290 LFI; CD40, 1101 vs 715 LFI; CD83, 433 vs 102 LFI; CD11c, 2642 vs
910 LFI) on DC grown in the presence of TSN. To evaluate the difference
between tumor-related and non-tumor-related effects of cell culture
supernatants, adherent PBMC also were cultured with GM-CSF and IL-4 in
the presence of supernatants from the nonmalignant lung fibroblast cell
line IMR90, or from cultured allogeneic PBMC. These supernatants had no
effect on maturing DC phenotype (results not shown).
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Corresponding to the early and heightened expression of APC markers, DC
exposed to TSN also displayed higher allostimulatory activity at day 4
compared with control DC. However, despite this early increase, the
degree of allostimulatory activity exhibited by TSN-DC did not reach
the maximal level exhibited by control DC, and decreased significantly
by day 7. In contrast, DC cultured under normal conditions showed a
consistent increase in allostimulatory activity between days 4 and 7,
corresponding to their continued maturation over the 7-day culture.
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Compared with control DC, TSN-exposed DC internalized only 63% as much
FITC-dextran on day 4, and only 50% as much FITC-dextran by day
7.
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Translocation of RelB to the nucleus, an event associated with DC
maturation (28, 29), was assessed by resolving nuclear and
cytoplasmic proteins on SDS-PAGE gels, followed by Western blotting.
Consistent with the increased allostimulatory activity of the TSN-DC on
day 4, there were high levels of RelB protein in both the cytoplasm and
nucleus, while only minimal levels were observed in control DC on day 4
(Fig. 4). However, by day 7, the levels
of RelB were greatly reduced in TSN-DC, while control DC showed
enhanced nuclear translocation of RelB, consistent with their slower
maturation.
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The ability of DC to produce IL-12 when stimulated through CD40 is
important for the generation of protective immunity. Stimulation with
the combination of CD40L and IFN- resulted in production of IL-12
p70 (the bioactive form of IL-12) by the control cells, but not by DC
exposed to TSN (Table II). The DC exposed
to TSN also were impaired in their ability to produce IL-10, but did
respond to stimulation by producing PGE2 at
levels equal to or greater than that produced by control DC.
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Viable cell yield was reduced in DC cultures containing TSN
(70 ± 1.4% of control, n = 4), leading us to
investigate the effect of TSN on DC apoptosis. As shown in Fig. 5, the percentages of both apoptotic
(51.4 vs 6.7%) and dead (24 vs 12.5%) cells were higher in the day 4
TSN-DC. It is unlikely that the apoptosis-inducing effect of TSN was
due to changes in cell culture pH or nutrient deprivation, since as
little as 1% TSN produced substantial increases in annexin binding
(Fig. 6, left panel). In
addition, supernatants from neither allogeneic PBMC nor the
nonmalignant lung fibroblast cell line IMR90 increased DC apoptosis.
The effects of TSN on DC apoptosis were not neutralized by Abs against
IL-10, VEGF, TGF-ß, or PGE2 (Table I
).
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TSN from a variety of tumor types induced DC apoptosis
TSN obtained from an additional lung cancer (A427), a breast
cancer (MCF-7), a renal cell carcinoma (R11), and a melanoma (M14) cell
line also were evaluated for their effect on DC maturation. At day 4 of
culture, TSN from all of the tumor cell lines induced similar levels of
apoptosis in DC (Fig. 6, right panel). None of the day 6
TSN-treated DC were capable of producing IL-12 at the same levels as
the control cells following stimulation with CD40L and IFN- (A427
and R11, <2 pg/ml; M14, 9 pg/ml), although MCF-7 TSN-treated DC did
produce moderate amounts (630 pg/ml). In addition, TSN from all of the
tumors enhanced expression of characteristic cell surface molecules
(Fig. 7), and resulted in cells with
enhanced allostimulatory activity at day 4 (data not shown), suggesting
that the immunomodulating effects mediated by A549 are shared by a
variety of tumor types.
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DC precursors exposed to TSN for only the first 24 h of
culture demonstrated altered maturation and apoptosis similar to that
observed with cells continuously exposed to TSN (Fig. 8). In contrast, DC precursors that were
allowed to mature for 7 days in GM-CSF and IL-4 before exposure to TSN
for 48 h resembled control DC (Fig. 9). These cells did not up-regulate
HLA-DR, CD80, or CD86, indicating that TSN does not act as a final
maturation factor like LPS, CD40L, and monocyte-conditioned medium
(30, 31, 32, 33, 34, 35). Therefore, the effects of TSN appear to be
maturation dependent, acting only on DC precursors and not mature
DC.
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It has been demonstrated that IL-12 protects DC from the induction
of apoptosis by anti-Fas Ab in vitro (36), and is
involved in the survival-enhancing effect of CD40 ligation in vivo
(37). Coupled with the lack of production of IL-12 by the
TSN-exposed DC, it is possible that exogenous IL-12 could have a
similar effect on the induction of apoptosis by TSN. We added a range
of IL-12 concentrations (0.2–100 ng/ml) to adherent PBMC at the
initiation of DC culture. As shown in Fig. 10, addition of IL-12 did not decrease
the level of apoptosis in the TSN-DC. No change was observed in the
expression of APC cell surface molecules (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC maturation is a coordinated process involving up-regulation of cell surface molecules, cytokine production, and functional activity (28). DC that fail to develop properly may be unable to stimulate Ag-specific T cells, or may promote the development of T cell anergy (13). It appears that TSN disrupts the maturation process by inducing monocyte DC precursors to develop some, but not all, of the characteristic properties of DC. The resulting DC, while appearing phenotypically mature, have functional defects that impact on their ability to stimulate specific T cell responses. In addition, TSN-exposed DC undergo apoptosis at an early time point, reducing the window of time during which they might interact with T cells in vivo. These effects of TSN on monocyte DC precursors are clearly different from those reported for CD34+ DC precursors. CD34+ cells exposed to TSN during DC maturation do not up-regulate CD80 and CD86 expression, develop only minimal HLA-DR expression, and never acquire significant APC activity (14, 15). The differential effects of TSN on maturation of DC from CD34+ and monocyte precursors suggest two distinct pathways by which tumors might suppress immune recognition.
Activation of the NF-B/RelB family and translocation of RelB from
the cytoplasm to the nucleus are associated with the maturation of DC
(28) and development of Ag-presenting activity
(29). Factors that prevent DC maturation from
CD34+ precursors also inhibit NF-B activity
and decrease RelB and c-Rel activation, consistent with the failure of
the cells to develop APC phenotype or functional activity
(16). Monocyte DC precursors exposed to TSN demonstrated
increased levels of both cytoplasmic and nuclear RelB. This increase
coincided with the rapid up-regulation of APC cell surface molecules
and activity, but levels diminished substantially by day 7,
corresponding to a reduction in functional activity. In contrast,
control DC reached their maximal levels of RelB expression at day 7,
corresponding to their slow, progressive development of APC cell
surface molecule expression and allostimulatory activity. Despite their
differences in response to TSN, the expression and translocation of
RelB appear to coincide with the acquisition of APC function in both
monocyte and CD34+-derived DC.
The number of DC infiltrating tumor sites has been correlated with
prognosis and survival (38). Many tumors have reduced
numbers of DC, and those DC that are present have low functional
activity (8, 9, 10, 11, 12, 13). Our data suggest that tumor-derived
factors induce monocyte-derived DC to undergo apoptosis early during
their maturation. Furthermore, the cells that remain viable at day 7
have reduced allostimulatory activity and do not produce IL-12, but
rather produce high levels of PGE2. The
functional consequences of these cytokine changes may be quite
important because a reduction in IL-12 levels may prevent stimulation
of Th1 T cell responses, and skew responding T cells toward a Th2
response (39, 40). In addition, IL-12 has been reported to
act as an antiapoptotic factor for DC (36, 37), and lack
of production by DC may contribute to early cell death. However, in our
hands, the addition of exogenous IL-12 was unable to prevent
TSN-induced DC apoptosis. Although TSN-exposed DC do not produce IL-10,
enhanced levels of PGE2 in the lung tumor
microenvironment have been shown to promote IL-10 production by T cells
and tumor cells (41). In the absence of IL-12 production
by the DC, increased levels of IL-10 may lead to the development of
Ag-specific anergy (42, 43). Other investigators have
compared the cytokine profiles of progressing and regressing metastases
obtained from the same patient, and have reported that progressing
metastases express high levels of IL-10, while regressing metastases
express IL-1, IFN-, and IL-12. DC from progressing metastases
induced anergy in CD4+ T cells, which could be
reversed by the addition of exogenous IL-12 or IL-2
(13).
Apoptosis is a tightly regulated process that occurs normally during cellular activation, maturation, and senescence. We observed DC apoptosis late in the maturation of control DC, and a similar outcome has been reported for activated T cells (44) and for DC induced to mature by bacterial engulfment (28). Apoptosis may serve an important role by removing cells after they have served their functional purpose and allowing the immune system to return to homeostasis. Our data suggest that tumor cells may take advantage of this process by promoting a premature apoptosis that destroys DC before they can effectively interact with T cells. Certain factors and events have been shown to promote the survival of mature activated DC, including exogenous IL-12, TRANCE, and CD40L (36, 45, 46), as well as survival signals provided by Ag-specific interactions with T cells (47). It is unclear whether these substances have the same antiapoptotic effect on developing DC, and an evaluation of their ability to counteract the effects of TSN will be the focus of further study.
The use of ex vivo generated DC to overcome the APC deficiencies in cancer patients is the rationale behind recent clinical studies. Methods have been developed to pulse DC with tumor Ags before readministration to the patient, with the hope that an increase in the number of functional tumor Ag-presenting DC will generate specific antitumor responses and immunity. Deleterious effects of tumors on readministered DC could have serious consequences for the efficacy of these treatments. Encouragingly, our results suggest that DC reach a maturation point at which TSN has little or no effect. Although early exposure results in dysfunctional maturation and apoptosis of DC, addition of TSN to day 7 DC did not induce phenotypic changes or apoptosis. Reports that DC prepared ex vivo from monocyte precursors were able to stimulate antitumor responses in patients are consistent with this observation (48, 49, 50).
In summary, tumors have at least two mechanisms by which they can alter DC maturation and function. The first, mediated by tumor-derived VEGF, M-CSF, and IL-6, affects CD34+ precursors by promoting the generation of immature DC that lack the cell surface phenotype and T cell stimulatory activity characteristic of mature, functional DC (14, 15). The second pathway, demonstrated in this study, is the ability of soluble tumor-derived factors to promote dysfunctional maturation and early apoptosis of DC developing from monocyte precursors. This ability was observed even at low TSN concentrations, and was common to a variety of tumor types. The cytokines IL-10, TGF-ß, and VEGF, which have been shown to have immunomodulatory effects on CD34+ and/or CD14+ DC precursors, are produced in picogram quantities by A549. However, the addition of neutralizing Abs to these factors did not block TSN-induced changes in phenotype and apoptosis. The factor(s) and mechanism responsible for these effects of TSN remain to be determined and are the focus of ongoing study. By acting on both CD34+ and monocyte DC precursors, tumors might effectively evade immune recognition and prevent the establishment of an antitumor T cell response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sylvia Kiertscher, UCLA School of Medicine, 37-131 CHS, Los Angeles, CA 90095-1690. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cells; LFI, linear fluorescence intensity; TSN, tumor supernatant; VEGF, vascular endothelial growth factor; CD40L, CD40 ligand.
Received for publication July 8, 1999. Accepted for publication November 18, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation in hemopoietic progenitor cells. J. Immunol. 160:1224.
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E. H. Slager, C. E. van der Minne, M. Kruse, D. D. Krueger, M. Griffioen, and S. Osanto Identification of Multiple HLA-DR-Restricted Epitopes of the Tumor-Associated Antigen CAMEL by CD4+ Th1/Th2 Lymphocytes J. Immunol., April 15, 2004; 172(8): 5095 - 5102. [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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E. Orsini, A. Guarini, S. Chiaretti, F. R. Mauro, and R. Foa The Circulating Dendritic Cell Compartment in Patients with Chronic Lymphocytic Leukemia Is Severely Defective and Unable to Stimulate an Effective T-Cell Response Cancer Res., August 1, 2003; 63(15): 4497 - 4506. [Abstract] [Full Text] [PDF]
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J. Peguet-Navarro, M. Sportouch, I. Popa, O. Berthier, D. Schmitt, and J. Portoukalian Gangliosides from Human Melanoma Tumors Impair Dendritic Cell Differentiation from Monocytes and Induce Their Apoptosis J. Immunol., April 1, 2003; 170(7): 3488 - 3494. [Abstract] [Full Text] [PDF]
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S. Sharma, M. Stolina, S.-C. Yang, F. Baratelli, J. F. Lin, K. Atianzar, J. Luo, L. Zhu, Y. Lin, M. Huang, et al. Tumor Cyclooxygenase 2-dependent Suppression of Dendritic Cell Function Clin. Cancer Res., March 1, 2003; 9(3): 961 - 968. [Abstract] [Full Text] [PDF]
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E. H. Slager, M. Borghi, C. E. van der Minne, C. A. Aarnoudse, M. J. E. Havenga, P. I. Schrier, S. Osanto, and M. Griffioen CD4+ Th2 Cell Recognition of HLA-DR-Restricted Epitopes Derived from CAMEL: A Tumor Antigen Translated in an Alternative Open Reading Frame J. Immunol., February 1, 2003; 170(3): 1490 - 1497. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, F. Koji, and F. Kawano Malignant counterpart of myeloid dendritic cell (DC) belonging to acute myelogenous leukemia (AML) exhibits a dichotomous immunoregulatory potential J. Leukoc. Biol., January 1, 2003; 73(1): 82 - 90. [Abstract] [Full Text] [PDF]
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 K. Mashino, N. Sadanaga, F. Tanaka, M. Ohta, H. Yamaguchi, and M. Mori Effective Strategy of Dendritic Cell-based Immunotherapy for Advanced Tumor-bearing Hosts: the Critical Role of Th1-dominant Immunity Mol. Cancer Ther., August 1, 2002; 1(10): 785 - 794. [Abstract] [Full Text] [PDF]
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C. C. Sombroek, A. G. M. Stam, A. J. Masterson, S. M. Lougheed, M. J. A. G. Schakel, C. J. L. M. Meijer, H. M. Pinedo, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4333 - 4343. [Abstract] [Full Text] [PDF]
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B. Laupeze, L. Amiot, L. Sparfel, E. Le Ferrec, R. Fauchet, and O. Fardel Polycyclic Aromatic Hydrocarbons Affect Functional Differentiation and Maturation of Human Monocyte-Derived Dendritic Cells J. Immunol., March 15, 2002; 168(6): 2652 - 2658. [Abstract] [Full Text] [PDF]
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K. Kato, Y. Takaue, and H. Wakasugi T-cell-conditioned medium efficiently induces the maturation and function of human dendritic cells J. Leukoc. Biol., December 1, 2001; 70(6): 941 - 949. [Abstract] [Full Text] [PDF]
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A. G. S. Buggins, D. Milojkovic, M. J. Arno, N. C. Lea, G. J. Mufti, N. S. B. Thomas, and W. J. R. Hirst Microenvironment Produced by Acute Myeloid Leukemia Cells Prevents T Cell Activation and Proliferation by Inhibition of NF-{kappa}B, c-Myc, and pRb Pathways J. Immunol., November 15, 2001; 167(10): 6021 - 6030. [Abstract] [Full Text] [PDF]
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T. Kanto, P. Kalinski, O. C. Hunter, M. T. Lotze, and A. A. Amoscato2 Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis J. Immunol., October 1, 2001; 167(7): 3773 - 3784. [Abstract] [Full Text] [PDF]
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D. J. Nelson, S. Mukherjee, C. Bundell, S. Fisher, D. van Hagen, and B. Robinson Tumor Progression Despite Efficient Tumor Antigen Cross-Presentation and Effective "Arming" of Tumor Antigen-Specific CTL J. Immunol., May 1, 2001; 166(9): 5557 - 5566. [Abstract] [Full Text] [PDF]
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C. Menetrier-Caux, M. C. Thomachot, L. Alberti, G. Montmain, and J. Y. Blay IL-4 Prevents the Blockade of Dendritic Cell Differentiation Induced by Tumor Cells Cancer Res., April 1, 2001; 61(7): 3096 - 3104. [Abstract] [Full Text]
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 S. M. Dubinett, R. K. Batra, P. W. Miller, and S. Sharma Tumor Antigens in Thoracic Malignancy Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 524 - 527. [Full Text]
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