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Immunology |
Departments of Surgery [L. A. L., G. R. G., M. M., R. J. B.] and Microbiology [B. D., R. J. N.], Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, New Hampshire 03756
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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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A number of studies in murine tumor models have shown that DCs pulsed with tumor antigens can generate effective antitumor immune responses in both established tumor and vaccine/challenge protocols (9, 10, 11, 12, 13, 14, 15, 16) . In these studies, DC vaccines have been administered either s.c., intradermally, or i.v., requiring the DCs to migrate to lymphoid organs for T-cell interaction. However, evidence shows that few transferred DCs actually reach lymphoid organs. In a study by Kupiec-Weglinski et al. (17) , only 1% of radiolabeled splenic DCs injected s.c. in the footpad of mice reached the draining popliteal lymph nodes. In a similar murine model, Lappin et al. (18) demonstrated a time- and dose-dependent accumulation of FITC-labeled bone marrow-derived DCs within draining popliteal lymph nodes after s.c. footpad injection. Despite injecting 6 x 105 DCs, the authors found a peak concentration, 48 h after injection, of only 52 DCs/million lymph node cells (approximately 90 DCs/lymph node; Ref. 18 ). In a study conducted in humans using radiolabeled DCs, <0.4% of the injection site activity was detectable in the regional lymph nodes after an intradermal injection, and no activity was detected after a s.c. injection (19) . Studies in murine (17 , 18 , 20 , 21) , primate (22) , and human (19) models have shown that DCs administered i.v. preferentially migrate to the spleen, with only trace or no migration to regional lymph nodes. However, <15% of i.v. administered DCs ultimately reach the spleen (17) . Therefore, conventional methods of DC-based immunization results in the delivery of only a small fraction of transferred DCs to lymphoid organs, where they can interact with T cells.
Another possible route of DC administration, which avoids the need for DC migration, is injection directly into lymph nodes. In a human study by Nestle et al. (23) , 16 patients with metastatic melanoma underwent vaccination with melanoma peptide-pulsed DCs via intranodal injection. After immunization, 11 of 16 patients developed a delayed-type hypersensitivity response to peptide-pulsed DCs. Five of 16 patients demonstrated a clinical response to the vaccine, including 2 complete responses and 3 partial responses. It is unclear whether these promising results are attributable to the route of DC injection or the composition of the vaccine. Therefore, we set out to test the hypothesis that direct injection of antigen-loaded DCs into lymph nodes will enhance the generation of antigen-specific T cells and protective antitumor immunity.
Although the studies described above have used immature DCs for immunization, recent reports suggest that ex vivo maturation of DCs will enhance their potency. Indeed, our lab initially demonstrated that stimulation of CD40 on DCs was required for the generation of protective cell-mediated tumor immunity by DC-based vaccines (24 , 25) . Labeur et al. (26) have gone on to show that CD40L-activated, tumor lysate-pulsed DCs more potently induced protective immunity than DCs prepared without CD40 activation. Human studies have shown that CD40 stimulation leads to the development of a more mature DC phenotype, with increased ability to stimulate allogeneic T-cell proliferation (27 , 28) . Because maturation of DCs can change the expression of multiple surface molecules, including chemokine receptors (29) , and influence DC migration (30) , we also compared the effectiveness of various routes of vaccination with CD40L-stimulated DCs.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Generation of Bone Marrow-derived DCs.
Bone marrow-derived DCs were generated as described previously
(13)
, with minor modifications. Briefly, bone marrow cells
flushed from tibias and femurs were depleted of erythrocytes by
incubating in 0.9% ammonium chloride for 3 min at 37°C. The cells
were washed in HBSS (Sigma Chemical Co., St. Louis, MO) and cultured in
CM (33)
with 10 ng/ml recombinant mouse GM-CSF (specific
activity, 7.42 x 107; kindly
provided by Immunex, Seattle, WA) and 20 ng/ml recombinant mouse IL-4
(PeproTech, Rocky Hill, NJ) at 1 x 106 cells/ml. On the fourth day in culture, the
media and floating cells were removed and centrifuged for 5 min at 1500
rpm. The cells were resuspended in CM at 1 x 106/ml with 10 ng/ml GM-CSF and 20 ng/ml IL-4 and
replaced in the original flasks. On day 7, nonadherent cells were
harvested by gentle pipetting. DCs were enumerated by FACS (FACScan;
Becton Dickinson, Mountain View, CA) analysis through the expression of
N418/CD11c-FITC (PharMingen, San Diego, CA). Preparations were
typically 40–50% positive for N418/CD11c and 70–80% positive for
MHC class II expression. Expression of the T-cell markers CD4 and CD8,
and the macrophage marker F4/80 was <5%.
Antigen Pulsing of DCs.
TS/A mammary adenocarcinoma and MCA-105 sarcoma cell suspensions
were prepared by enzymatic digestion in HBSS with 1% collagenase
(Sigma) and 0.1% hyaluronidase (Sigma). Tumor lysates were prepared by
three cycles of liquid nitrogen and 37°C water-bath freeze-thawing.
Day 6 DCs were incubated with tumor lysates at a ratio of 2.5:1 tumor
cell equivalents:DCs overnight at 37°C in CM, as described previously
(13)
. DCs were harvested by gentle pipetting and washed
twice in HBSS. DCs were resuspended in HBSS at specific vaccine
concentrations for use in further studies.
For DCs pulsed with both tumor lysate and CD40L, day 5 DCs were incubated for 4 h at 37°C with tumor lysate as described above. CD40L was generated as described previously (Ref. 34 ; a kind gift from Dr. Marilyn Kehry, IDEC Pharmaceuticals, La Jolla, CA) then added to the culture at 4% volume for 48 h. Treatment of DCs in this manner up-regulates CD80, CD86, and class II and enhances induction of T-cell proliferation in a mixed lymphocyte reaction (data not shown). The DCs were then harvested and prepared in HBSS as described above.
For DCs pulsed with ovalbumin peptides 323–339 (ISQ) and 357–364 (SNF; Research Genetics, Inc., Huntsville, AL), day 5 DCs were incubated at 37°C in CM with the peptides at 50 µg/ml for 90 min. The cells were harvested and washed three times with HBSS and then resuspended at 1 x 106 cells/ml in CM with 10 ng/ml GM-CSF and 20 ng/ml IL-4. CD40L DC pulsing occurred as described above. The cells were incubated in CM with 10 ng/ml GM-CSF and 20 ng/ml IL-4 at 37°C until day 7 and then harvested and prepared as described previously.
In Vivo Immunization and Tumor Challenge.
BALB/c or C57BL/6 mice were immunized by one of four different routes
of vaccine administration: s.c., i.v., intrasplenic, or intranodal.
Varying doses of DC vaccine were administered as indicated in the
figures. All treatment groups contained six to eight mice. All mice
were anesthetized with 0.75 mg i.p. of sodium pentobarbital. S.c.
administered vaccines were injected on the right flank, and i.v.
vaccines were administered through tail-vein injections. All intranodal
vaccines were administered into the inguinal lymph nodes. This
procedure was performed by making a vertical midline incision in the
skin of the abdomen and exposing the inguinal lymph nodes by gently
peeling the peritoneum away from the lateral abdominal wall. Using a
30-gauge needle (Becton Dickinson) and a 100-µl glass syringe, 10
µl of DC vaccine were injected into each inguinal lymph node. The
midline incision was closed primarily with a running absorbable suture.
Intrasplenic immunizations were performed through a small incision in
the left flank. Upon visualization, the tip of the spleen was exposed
through a small incision in the peritoneum, and 20 µl of DC vaccine
were injected through a 30-gauge needle. The peritoneum and skin were
closed primarily in separate layers with absorbable suture.
Seven days after immunization, the mice were challenged with a lethal dose of 5 x 105 viable TS/A (for BALB/c mice) or MCA-105 (for C57BL/6 mice) by i.v. tail-vein injection. Fourteen days later, the mice were sacrificed, and pulmonary metastases were detected as described previously (35) . Metastases were enumerated under the dissecting microscope by a single counter who was blinded as to the treatment status. Data are reported as the mean number of pulmonary metastases ± SE. Comparisons between the means were made using the Wilcoxon rank sum test.
Detection of DCs in Lymph Nodes.
Inguinal lymph nodes of three C57BL/6 mice were injected in
vivo or removed and injected ex vivo with 5 x 105 DCs prepared from congenic
C57BL/6-Ly5.2 mice. Immediately after the injection, a single-cell
suspension of the lymphocytes were prepared, and the Ly5.2 DCs were
enumerated through the positive coexpression of N418/CD11c-FITC and
CD45.1 (A.20)-PE (PharMingen) by FACS analysis.
Antigen-specific T-lymphocyte Proliferation and Function.
Spleens and lymph nodes were obtained from naïve OT-I and
OT-II mice. Single-cell suspensions were made and depleted of
erythrocytes. Transgenic OT-I CD8+ T lymphocytes, specific for
ovalbumin 257–264 peptide (SNF), were enumerated by FACS analysis
through the positive coexpression of CD45.1(A.20) (PharMingen),
V
2(B2.1) (PharMingen) and CD8 prepared from the hybridoma 53–6.7
(PharMingen). Transgenic OT-II CD4+ T lymphocytes, specific for
ovalbumin peptide 323–339 (ISQ), were enumerated through the positive
coexpression of V2 (B2.1) (PharMingen), Vß5(MR9–4) (PharMingen)
and CD4 (L3T4). Groups of three C57BL/6 mice received i.v. tail-vein
injections with 2.5 x 106 OT-I
CD8 and 2.5 x 106 OT-II CD4 T
lymphocytes. The following day, 1 x 106 ISQ-pulsed and SNF (+/- CD40L)-pulsed
C57BL/6 DCs were administered either s.c., i.v., or intranodally. Five
days later, the mice were sacrificed, spleens and popliteal and
inguinal lymph nodes were removed, and single-cell suspensions were
made. The OT-I CD8 and OT-II CD4 T lymphocytes were identified using
flow cytometry as described above. The data are reported as the
mean ± SE. Comparisons of the means were made using the
Mann-Whitney test.
Antigen-specific T-lymphocyte function was then evaluated by plating
2 x 105 splenocytes from each
treatment group with 1 x 105
irradiated naïve splenocytes in 100 µl of serum-free RPMI
1640/well on a 96-well plate. The cells were plated either
alone, with 50 µg/ml ISQ, or with 50 µg/ml SNF. The cells were
incubated for 24 h at 37°C. The plates were centrifuged for 2
min at 1000 rpm to pellet the cells, and the supernatants were
harvested and assayed for the production of IFN-
by ELISA using
unconjugated rat antimouse IFN- and a biotinylated anti-IFN-
antibody (PharMingen). ELISAs were developed using
streptavidin-horseradish peroxidase (Amersham, Arlington Heights, IL)
and tetramethylbenzidine substrate (Sigma). Comparison of the means was
made using a paired t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We next assessed the influence of the route of immunization on the
ability of a tumor lysate-pulsed DC vaccine to induce protective
antitumor immunity. C57BL/6 mice were immunized either intranodally or
s.c. with a high (10 x 105) or
low (2.5 x 105) dose of MCA-105
lysate-pulsed DCs. As shown in Fig. 1
, all four treatment groups showed significant antitumor immunity
compared with nonimmunized mice (P 
0.04).
Mice immunized intranodally with the high-dose vaccine were the most
effective at preventing the growth of MCA-105 pulmonary metastases
(1.7 ± 1), whereas those immunized s.c. with the
low-dose vaccine were the least effective (85 ± 35).
Intranodal injection of the vaccine was more effective than s.c. at
both the low dose (P = 0.04) and the high
dose (P = 0.04). Intranodal injection of
2.5 x 105 DCs generated
equivalent protective immunity as 1 x 106 DCs injected s.c., indicating that the
efficacy of intranodal immunization is 
4-fold greater than s.c. This
experiment was repeated three times with similar results.
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demonstrates the effectiveness of intranodal, s.c., and i.v.
immunization at two different vaccine doses. At the low dose (Fig. 2A)
, only mice immunized intranodally showed significant
antitumor immunity compared with nonimmunized mice
(P = 0.01). In addition, mice immunized
intranodally were significantly better at preventing the development of
pulmonary metastases than mice immunized s.c. (P = 0.02) or i.v. (P = 0.01). At the
higher dose (Fig. 2B)
, all three treatment groups showed
significant antitumor immunity compared with nonimmunized mice
(P 0.01). Again, mice immunized
intranodally developed significantly fewer pulmonary metastases when
compared with mice immunized s.c. or i.v. (P = 0.05 and 0.02, respectively). There was no significant
difference in the ability of mice immunized s.c. compared with i.v. to
prevent the development of TS/A pulmonary metastases
(P = 0.72).
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A, C57BL/6 mice receiving either an intrasplenic or
intranodal immunization with MCA-105 tumor lysate-pulsed DCs showed
significant antitumor immunity compared with nonimmunized mice
(P = 0.02 and 0.03, respectively.) No
significant difference was discerned between these two routes of
immunization (P = 0.16). Similarly, BALB/c
mice immunized either intrasplenic or intranodal with TS/A tumor
lysate-pulsed DCs also showed significant antitumor immunity compared
with nonimmunized mice (P = 0.04 and 0.01,
respectively; Fig. 3B
). Again, no significant difference was
discerned between these two routes of immunization
(P = 0.31).
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A, less than 1 x 105
transgenic T lymphocytes were detected in the spleens of nonimmunized
mice. A similarly low number of transgenic T lymphocytes were detected
in the spleens of mice immunized either intranodally or i.v. with
unpulsed DCs (data not shown). Significant transgenic CD8 T-lymphocyte
expansion was found in the intranodal, i.v., and s.c. antigen-loaded DC
vaccine groups as compared with nonimmunized mice (Fig. 4A
;
P < 0.05). In mice immunized intranodally,
the number of transgenic CD8 T lymphocytes recovered from the spleens
(120 x 105 ± 13 x 105) was 2.4 times greater
than the number recovered from the spleens of mice immunized i.v.
(51 x 105 ± 4.6 x 105; P < 0.05) and 6.3 times greater than mice immunized s.c.
(19 x 105 ± 3.2 x 105; P < 0.05). Transgenic CD8 expansion was also significantly greater
in mice immunized i.v. as compared with mice immunized s.c.
(P < 0.05).
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; P < 0.05). CD4 transgenic T
lymphocyte expansion was significantly greater after intranodal or i.v.
immunization compared with s.c. (P < 0.05);
however, there was no significant difference between intranodal and
i.v. immunization (P = 0.28). These
experiments were repeated twice with similar results.
Fig. 4B
shows transgenic CD8 and CD4 T lymphocytes recovered
from the inguinal and popliteal lymph nodes of transgenic T-lymphocyte
reconstituted mice immunized with ISQ- and SNF-pulsed DCs. Both CD8 and
CD4 transgenic T-cell proliferation was significantly greater after
intranodal, i.v., or s.c. immunization compared with nonimmunized mice
(P < 0.05). CD8 and CD4 transgenic T-cell
expansion was significantly greater in mice immunized intranodally
compared with mice immunized i.v. or s.c. (P < 0.05). There was no significant difference in antigen-specific
T-cell proliferation between mice immunized i.v. compared with s.c.
(P 
0.13).
We then evaluated the splenocytes of immunized mice for the presence of
an antigen-specific TH-1 cytokine response to peptide. Transgenic
SNF-specific CD8 and ISQ-specific CD4 T lymphocytes were adoptively
transferred. One day later, mice were immunized intranodally, i.v., or
s.c. with either unpulsed or peptide-pulsed DCs, and splenocytes were
harvested on day 5. The splenocytes were then either left unpulsed or
pulsed with ISQ or SNF peptides overnight, and the supernatants were
assayed for IFN- (Fig. 5)
. Although we observed significant proliferation of CD4 (OT-II) T cells
in the spleen when peptide-pulsed DC vaccine was administered
intranodally, i.v., or s.c. (Fig. 4A)
, we did not detect
IFN- secretion from ISQ-pulsed splenocytes. In contrast, SNF-pulsed
splenocytes from mice immunized intranodally with antigen-pulsed DCs
produced significant amounts of IFN- compared with splenocytes from
nonimmunized mice (P = 0.001; Fig. 5
). This
was not attributable to nonspecific antigen presentation, because
splenocytes from mice immunized with nonpulsed DCs did not secrete
IFN- (Fig. 5)
. Splenocytes from mice immunized intranodally with
antigen-pulsed DCs produced 25 times as much IFN- as mice immunized
i.v. (P = 0.02) and 31 times more IFN-
than mice immunized s.c. (P = 0.01). When
normalized for the number of OT-1 T cells/well, splenocytes from mice
immunized intranodally secreted 6.25 times more IFN- than mice
immunized i.v. These findings indicate that intranodal injection of
peptide-pulsed DCs stimulated significantly greater expansion of
antigen-specific CD8 T cells that were 6-fold more effective at
generating a TH-1 cytokine response than i.v. immunization.
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, compared with nonimmunized mice, both treatment groups showed
significant antitumor immunity against a lethal i.v. challenge of live
TS/A tumor cells (P = 0.01). Mice immunized
intranodally were significantly better at suppressing the development
of pulmonary metastases than those immunized s.c.
(P = 0.02).
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, relative to nonimmunized mice, significant CD8 and CD4 transgenic
T-cell proliferation was observed in the spleens of mice immunized
either intranodally or s.c. with the CD40L-stimulated DC vaccine
(P < 0.05). CD8 and CD4 antigen-specific
T-cell expansion in the spleens of mice immunized intranodally was
8-fold higher than mice given the same vaccine s.c.
(P < 0.05). Expansion of transgenic CD8 and
CD4 T cells in the lymph node was also significantly increased after
intranodal immunization compared with either nonimmunized mice or mice
immunized s.c. (P < 0.05).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
We are not aware of any other published murine studies evaluating
intranodal immunization. Our study shows that immunization of mice with
intranodal injections of tumor lysate-pulsed DCs could induce antitumor
immunity and resulted in significantly better antitumor protection
against pulmonary metastases compared with mice immunized s.c. or i.v.
(Figs. 1
and 2)
. In addition, our data indicate that the potency of
protective immunity induced by intranodal immunization is 4-fold higher
than s.c. immunization. These in vivo antitumor effects were
observed in two different strains of mice (C57BL/6 and BALB/c) against
two histologically distinct, syngeneic tumors (MCA-105 sarcoma and TS/A
adenocarcinoma), indicating that it is a generalizable observation.
To understand the mechanism for the enhanced efficacy of
intranodal vaccination, we compared the effect of various routes
of vaccine administration on their ability to generate antigen-specific
T lymphocytes with a TH-1 cytokine profile. Previous experiments in our
laboratory have shown that IFN- secretion by CD8 lymphocytes is
required for therapeutic effectiveness against established
micrometastases (33)
. Our results using the transgenic
OT-I/OT-II system show that intranodal immunization dramatically
increases the generation of antigen-specific CD8 and CD4 lymphocytes
compared with i.v. or s.c. DC immunization. Furthermore,
antigen-specific secretion of IFN- by the expanded T cells after
intranodal immunization was >6-fold greater than i.v. immunization on
a cell-to-cell basis. Intranodal immunization may be more effective
than other routes simply because it is a reliable method for getting
more DCs to contact T lymphocytes in a lymphoid environment than other
methods of immunization. We are also currently evaluating the effect of
intranodal immunization on DC trafficking and survival.
We have demonstrated that the route of DC vaccine administration has a quantitative effect on the development of a TH-1 T-cell response. Others have shown that the route of DC vaccine administration may have a qualitative influence on the TH-1/TH-2 cytokine response profile. In a study by Morikawa et al. (39) , using reverse transcription-PCR to measure the presence of mRNA of various cytokines in mouse spleen and lymph node cells, keyhole limpet hemocyanin-pulsed, bone marrow-derived DCs were shown to stimulate a TH-1 cytokine response in the draining lymph nodes when administered s.c. and a TH-2 cytokine response when administered i.v. We are currently evaluating the effect of the route of vaccine administration on the pattern of cytokine production by lymphocytes in the transgenic ovalbumin system.
Evidence is accumulating from both murine and human studies that maturation of DCs through CD40 stimulation leads to more potent T-lymphocyte activation. We initially demonstrated that CD40 triggering was necessary for the generation of protective cell-mediated tumor immunity by both DC-based and adjuvant-based vaccines (24 , 25) . A study by Labeur et al. (26) has also shown that CD40L-activated, tumor lysate-pulsed DCs led to more potent induction of protective immunity than DCs prepared without CD40 activation. Human studies using DCs generated from peripheral bone marrow cells cultured in GM-CSF and IL-4 have shown that CD40 stimulation leads to the development of a more mature DC phenotype and increased ability to cause allogeneic T-cell proliferation in a mixed lymphocyte reaction (28) . Others have shown that CD40L stimulation of DCs will enhance allogeneic T-cell proliferation and lead to the generation of DCs that are able to induce peripheral bone marrow cells to lyse autologous leukemia cells (27) . As with non-CD40L-stimulated DCs, our data show that intranodal immunization with tumor lysate-pulsed, CD40L-stimulated DCs induces significantly greater antitumor immunity in a murine protection/challenge model compared with s.c. immunization. Furthermore, CD40L-stimulated, antigen-loaded DCs administered intranodally were also capable of inducing significantly more antigen-specific CD4 and CD 8 T-cell proliferation in both the spleen and lymph nodes compared with nonimmunized mice and mice immunized s.c.
In summary, we have demonstrated that intranodal injection of both mature and immature DC tumor vaccines generates a more potent antitumor immune response than conventional s.c. or i.v. routes of vaccination. These results are directly applicable to the design of DC-based tumor vaccine studies in patients.
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FOOTNOTES |
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1 Supported by 1R29CA776612-01 (to R. J. B.) and
by the Hitchcock Foundation. 
2 To whom requests for reprints should be
addressed, at Section of General Surgery, Dartmouth Hitchcock Medical
Center, Lebanon, NH 03756. Phone: (603) 650-7903; Fax:
(603) 650-8030; E-mail: Richard.J.Barth.Jr{at}Dartmouth.edu
3 The abbreviations used are: DC, dendritic cell;
CM, complete medium; GM-CSF, granulocyte/macrophage-colony stimulating
factor; IL, interleukin; FACS, fluorescence-activated cell sorter;
CD40L, CD40 ligand.
Received 6/ 5/00. Accepted 11/14/00.
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A. E. Chang, B. G. Redman, J. R. Whitfield, B. J. Nickoloff, T. M. Braun, P. P. Lee, J. D. Geiger, and J. J. Mule A Phase I Trial of Tumor Lysate-pulsed Dendritic Cells in the Treatment of Advanced Cancer Clin. Cancer Res., April 1, 2002; 8(4): 1021 - 1032. [Abstract] [Full Text] [PDF]
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