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Advances in Brief |
Department of Oncology and Surgical Sciences University of Padova, 35128 Padova, Italy [V. B., E. A., R. R., P. Z., P. Z.], and Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [W. W. O., D. R. S, N. P. R.]
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-chain, suggesting a scenario in which melanoma
cells targeted by specific antibodies were eliminated by
antibody-dependent cellular cytotoxicity-mediated lysis
(6, 7, 8, 9)
. Induction of an effective immune response against
TRP-1/gp75 was associated with autoimmune manifestations consisting of
diffuse depigmentation of skin patches (vitiligo) attributable to the
destruction of normal melanocytes sharing the TRP-1/gp75 Ag. Additional
studies are required to understand the association between vitiligo and
melanoma therapy, because the mechanisms inducing vitiligo could be
uncoupled from those causing tumor regression in one study but not in
another (5
, 7) . Although the immune response to TRP-1/gp75 is dominated by production of anti-TRP-1/gp75 antibodies, TRP-2 Ag is the main target of murine CTLs generated after immunization with irradiated melanoma cells (10) ; CTL lines raised from splenocytes by repeated in vitro stimulation with the "self," immunodominant TRP-2 peptide showed therapeutic activity against established pulmonary metastases. On the other hand, active immunization with DNA encoding murine trp-2 administered using a gene gun in association with a plasmid encoding interleukin 12 was capable of eliciting CTLs recognizing B16 melanoma but induced only a weak protective response (11) . The present study demonstrates that i.m. immunization with plasmid DNA encoding murine trp-2 conferred protection to challenge with B16 melanoma cells; moreover, administration of a rVV encoding murine trp-2 was therapeutic in tumor-bearing mice. In contrast to mice immunized with TRP-1/gp75, the main effector populations induced by DNA immunization with the trp-2 gene and involved in tumor protection were CD8+ lymphocytes and NK1.1+ cells. Furthermore, mice that rejected the tumor did not develop generalized vitiligo during the observation period but exhibited depigmentation and hair loss localized at the site of tumor inoculation. Active immunization with trp-2-encoding vectors may thus represent a promising immunotherapy strategy against melanoma.
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Materials and Methods |
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Cell Lines.
MBL-2 is a leukemia cell line (H-2b) derived from
a Moloney murine leukemia virus-infected B6 mouse; C57BL/6 is a
melanoma line (H-2b) spontaneously growing in
C57BL/6 mice (kindly provided by Dr. I. J. Fidler, M. D. Anderson
Cancer Center, Houston, TX). The cell lines were cultured in DMEM (Life
Technologies, Inc., Gaithersburg, MD) supplemented with 2
mM L-glutamine, 10 mM HEPES, 20
µM 2-mercaptoethanol, 10 units of ampicillin/ml, and 5 or
10% heat-inactivated fetal bovine serum (Life Technologies).
Plasmid and Viruses.
The cDNA coding for murine trp-2 was a kind gift of Dr.
V. J. Hearing (Laboratory of Cell Biology, NIH, Bethesda, MD;
Ref. 13
). The trp-2 gene was cloned into the
eukaryotic expression plasmid pcDNA3 (Invitrogen BV, Leek, the
Netherlands), resulting in plasmid pcDNA3- trp-2, in which
expression of the mouse trp-2 gene is driven by the
cytomegalovirus promoter/enhancer. Endotoxin-free plasmids were
purified by anion exchange chromatography (Qiagen GmbH, Hilden,
Germany). rVV-trp-2 was generated by insertion of the
trp-2 gene by homologous recombination as described
previously by Moss and Earl (14)
and was derived using
plasmid pSC65, in which the completely synthetic early/late promoter
pSE/L drives expression of the Ag and the
early/late promoter p7.5E/L drives expression of
the LacZ gene (14)
. Expression of TRP-2 protein
by rVV-trp-2 and by pcDNA3- trp-2 was confirmed
by immunostaining of infected/transfected cells using anti-TRP-2 serum
(anti-PEP8 serum, kindly provided by Dr. V. J. Hearing).
DNA and Recombinant Virus Immunization Protocols.
DNA immunization was performed according to commonly used protocols
available at the "DNA vaccine web"
site.4
Briefly, mice were anesthetized by ethyl ether inhalation and injected
i.m. with 100 µl of 10 µM cardiotoxin (Latoxan, Rosans,
France). Five to 9 days later, mice were injected i.m. with 100 µg of
plasmid DNA in 100 µl of saline. rVV (5 x 106 PFU/mouse) was inoculated i.v. 5 days after
tumor injection.
MLPC.
Three weeks after plasmid DNA inoculation, spleens were removed, and
2.5 x 107 splenocytes were
stimulated in vitro in a MLPC with 1
µM of a nonamer peptide corresponding to amino
acids 180–188 of TRP-2 (SVYDFFVWL; Refs. 10
and
11
); the peptide was synthesized and purified by Neosystem
(Strasbourg, France). The cultures were set up in DMEM-10% fetal
bovine serum, maintained for 5 days at 37°C under 5%
CO2, and then tested in
51Cr and IFN- release assays. Cytotoxic
activity of cultured splenocytes was tested in a short-term incubation
51Cr release assay by mixing 2 x 103 51Cr-labeled target cells with
the effector cells at various E:T cell ratios in 96-well microplates;
after 5 h of incubation at 37°C, supernatants were harvested,
and radioactivity was counted in a microplate scintillation counter
(Packard Instruments Co., Meriden, CT). For peptide pulsing,
106 51Cr-labeled cells were incubated for 30 min
at 37°C with 1 µM peptide and then washed
before use. The IFN- release assay was carried out by restimulating
105 splenocytes from MLPC for 24 h in
triplicate wells with an equal number of target cells; the supernatant
was then harvested and tested for released IFN- in a sandwich ELISA
assay (Endogen, Boston, MA).
Tumor Protection and Therapy.
Three weeks after DNA inoculation, mice were challenged s.c. with a
lethal dose of B16 melanoma cells (i.e.,
105 cells, 10-fold greater than the minimum
tumorigenic dose), and then monitored for 120 days after tumor
injection. Mice inoculated with mock plasmid and uninoculated mice were
used as control groups. For tumor therapy experiments,
105 B16 cells were injected s.c. 5 days before
rVV inoculation.
In Vivo Antibody-mediated Depletion.
Mice were depleted of either CD4+,
CD8+, or NK cells by four i.p. injections of 200
µg of GK1.5 (anti-CD4), 2.43 (anti-CD8), or PK136 (anti-NK1.1)
monoclonal antibodies (mAb) prepared in 200 µl of endotoxin-free PBS
(Sigma). Depleting mAb were given on days -2, 0, 4, and 8 with respect
to the s.c. challenge with B16 melanoma cells. The mAbs were produced
from hybridomas (obtained from American Type Culture Collection,
Manassas, VA) grown in ascites and purified by ammonium sulfate
precipitation, followed by protein-G Sepharose affinity chromatography
(Pharmacia, Uppsala, Sweden). Depletion was monitored by
cytofluorimetry of peripheral lymphocytes isolated from mouse blood and
stained with FITC- or PE-conjugated anti-CD4, anti-CD8, or anti-NK1.1
(clones RM4-5, 53.6-7, and 2B4, respectively; all from PharMingen, San
Diego, CA). Depletion was consistently >98%.
Statistical Analysis.
The Wilcoxon-Mann-Whitney U test was used to examine the
null hypothesis of rank identity between two sets of data. Kaplan-Maier
plots and the Mantel-Haenszel test were used to compare survival of
mice belonging to different treatment groups. All Ps
presented are two sided.
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Results |
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. CTL activity against MBL-2 cells pulsed with
TRP-2180–188 peptide was present only in mice
injected with DNA expressing TRP-2. Peptide-specific CTLs were not
elicited in control mice that received cardiotoxin alone or cardiotoxin
followed by plasmid pcDNA3. Although CTLs specifically recognized the
TRP-2 immunodominant peptide, they were not able to efficiently lyse
B16 tumor cells.
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prior to the
51Cr assay (11)
; alternatively, the
levels of IFN- released in the supernatant of CTL cultures
stimulated for 24 h can be measured. Fig. 1B
shows
IFN- release assay of MLPC set up with splenocytes from mice
immunized with pcDNA3-trp-2 or pcDNA3 and either B16 tumor
cells or TRP-2180–188 peptide-pulsed MBL-2 cells
as targets. Results showed that elevated amounts of IFN- were
detected in the supernatants of lymphocytes cultured in the presence of
either target, thus indicating that the DNA protocol is indeed capable
of eliciting CTLs specifically recognizing the B16 melanoma.
DNA Immunization with pcDNA3-trp-2 Protects from Challenge with B16
Melanoma Cells.
The release of IFN- by CTLs as an indicator of immune response was
shown previously to correlate with the in vivo antitumor
activity of the CTLs upon adoptive transfer (15)
. We thus
asked whether the Ag-specific response demonstrated in mice immunized
with pcDNA3-trp-2 could protect them from tumor challenge.
Fig. 2
summarizes results of five experiments in which naïve mice or
mice previously immunized with pcDNA3-trp-2 were injected
with a lethal dose of B16 melanoma cells. Although control mice left
untreated died within 3 weeks after challenge, almost complete
protection against the lethal challenge was achieved in mice vaccinated
with the plasmid DNA encoding trp-2. Data accumulated from
the five experiments yielded an overall rate of tumor prevention of
86% (i.e., 36 of 42 mice were protected). Unexpectedly,
untreated mice and mice injected with the empty pcDNA3 vector also
showed a significant difference in survival, suggesting a marginal,
Ag-independent effect of DNA immunization in prevention of tumor
growth. This effect was related to the pcDNA3 vector, because it was
not observed with a second construct derived from the plasmid VR1012
(Ref. 16
; data not shown).
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, DNA immunization increased the survival of both normal
mice and mice depleted of CD4+ lymphocytes,
indicating that CD4+ cells were not required to
control B16 melanoma growth. In contrast, mice depleted of either
CD8+ lymphocytes or NK cells were no longer
protected and succumbed from tumor challenge. Thus, both
CD8+ lymphocytes and NK cells acted in concert to
eradicate melanoma cells in immune mice.
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). Haircoat loss was clearly evident 3 weeks after tumor
challenge when the hair grew back in the shaved left flank, with the
exception of the tumor injection site. The haircoat alterations were
observed in 
40% (15 of 36) of all of the mice that survived the
challenge, and they remained stable for the observation period of 1
year.
Immunization with rVV Encoding trp-2 Can Cure
Established Tumors.
The high rate of protection against B16 melanoma conferred by a DNA
vaccine coding for TRP-2 Ag prompted us to investigate its therapeutic
ability against established tumors. However, application of the same
DNA immunization protocol used in the protection experiment did not
result in tumor regression (data not shown). We speculated that the
time required for optimal CTL generation after DNA immunization (2
weeks, not shown) was too long to allow a successful treatment of a
swiftly growing tumor such as B16 melanoma, which is able to kill the
host in 3–4 weeks. Therefore, we turned to an rVV vector as a means of
expressing the TRP-2 Ag. In the hope that it might reduce the lag phase
between vaccination and CTL production, mice were injected with a
lethal dose of B16 tumor cells and 5 days later received 5 x 106 PFU of either mock rVV or
rVV-trp-2 (Fig. 4
). As expected, negative control mice that were untreated or injected
with the mock rVV died within 3–4 weeks after tumor challenge.
In contrast, 50% of the mice that were treated with
rVV-trp-2 remained tumor free 3 months after inoculation
with B16 cells. These mice did not show any signs of vitiligo and did
not exhibit the changes in pigmentation and haircoat noted in
pcDNA3-trp-2-vaccinated mice. The reasons for these
differences are not clear. We hypothesize that NK cell activation
induced by DNA immunization might help in causing more extensive tissue
destruction. Moreover, immunization after tumor implantation
might affect a population of CTL preprimed by the encounter with the
tumor cells that is already highly specific for TRP-2. Immunization
before tumor challenge might expand largely cross-reactive CTLs
responsible for an higher degree of cross-killing and tissue
devastation.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The choice of the vaccine is as important as the choice of the tumor Ag, because the formulation and the route of delivery may profoundly influence the immune responses. We sought to understand whether the therapeutic responses induced by rVV or by naked DNA were qualitatively different. DNA vaccines are thought to be less efficient than recombinant viruses in the therapy of established tumors expressing a model tumor Ag (19 , 20) . However, we urge caution in interpreting the finding of the reduced efficacy of DNA vaccination in a therapeutic setting (as described in the present report). Clearly, the decreased efficacy after vaccination with DNA could be entirely attributable to the long time required to elicit TRP-2-specific CTLs.
The association between autoimmune disorders, i.e., vitiligo and tumor regression described in mice immunized with TRP-1/gp75 Ag and in melanoma patients undergoing therapy with high doses of interleukin 2, has led to the suggestion that a deliberate induction of autoimmunity against tissue Ags may be an acceptable side effect of tumor therapy (21) , especially in the case of tumors arising from nonessential tissues. Our study indicates that diffuse vitiligo is not invariably associated with tumor eradication caused by immunization with MDAs and instead appears to depend on the specific Ag used. Some mice immunized with TRP-2 showed localized hair loss and depigmentation, likely sequelae to the inflammatory response and residual fibrosis accompanying the immune destruction of tumor cells and adjacent tissues. The observation that the presence of TRP-2-specific CTLs did not lead to generalized destruction of normal melanocytes supports the hypothesis that the pathogenesis of human vitiligo in melanoma patients is related more to antibodies recognizing melanoma proteins such as tyrosinase or TRP-1/gp75 rather than CTL activity (8 , 22) . Cutaneous lesions similar to those described in the present study were described recently in mice treated with a protocol consisting of immunization with a granulocyte/macrophage-colony stimulating factor-expressing melanoma vaccine, followed by inoculation with an mAb blocking the activity of the CTL-associated antigen 4; the combined treatment caused melanoma rejection which, analogous to our findings, was dependent on CD8+ and NK1.1+ cells but independent of CD4+ T cells (23) . About half of the mice surviving tumor challenge after combination treatment developed depigmentation, starting at the site of vaccination or challenge and spreading to distant sites; the initial lesions were similar to those observed after immunization with TRP-2-encoding plasmids. Because we did not observe vitiligo progression, it is conceivable that the CTL-associated antigen 4 blockade used in the previous study enhanced T-cell activation and triggered a massive proliferation of autoreactive T cells, the numbers of which are normally contained by the mechanisms of peripheral tolerance. Thus, although unleashing the mechanisms controlling the magnitude of the immune response may be relevant for enhancement of therapeutic efficacy, it must be weighed against the cost of an autoimmunity sequela.
We used CB6 F1 mice in the present experiments for several reasons:
(a) C57BL/6 mice lack a portion of the genome that contains
the 
chain of the I-E molecule, a condition that related to the
human beings would translate in the loss of the DR locus and
might affect the immune response to melanoma Ags; and (b)
F1 hybrids are heterozygous at the H-2 locus and thus closer
to patients who display an extreme polymorphism in HLA loci.
Experimentally, F1 mice showed anti-TRP-2 immune responses
stronger than that observed in C57BL/6 mice after DNA immunization. The
autoimmune and antitumor responses are currently being compared in
C57BL/6 and CB6F1 mice. Preliminary results indicate that differences
in T-lymphocyte repertoire directed against the
Kb-TRP-2 peptide complex might explain the
different magnitudes of the immune responses in the two strains.
In contrast to the highly efficient protection afforded by immunization with artificial model tumor-associated antigens such as ß-galactosidase (19 , 20) , protection against tumor challenge was not observed in the totality of the mice immunized with the trp-2-expressing plasmid. These differences almost certainly reflect the stronger immunogenicity of the model tumor Ags as compared with self Ags. Similar findings were made in our previous studies with the murine Ag P1A, which is naturally expressed in P815 mastocytoma cells (24) ; although vaccination of mice with a plasmid expressing P1A considerably increased their survival rate after challenge with P815 cells, it did not confer complete protection. Several strategies to increase the efficacy of DNA immunization are currently being evaluated. Although repeatedly boosting the immune response is the simplest approach, it cannot be based on repeated i.m. inoculation of DNA in cardiotoxin-pretreated muscles. In fact, we did not observe any increase in the percentage of mice rejecting a B16 challenge after two DNA inoculations instead of a single immunization (data not shown). A promising approach is the use of a DNA vaccine for priming and the modified vaccinia virus Ankara for boosting, a protocol that has been used successfully to increase the CTL response against malaria Ags (25) . Alternatively, combining different weak, self Ags in the same immunization protocol might increase the overall immune response against the tumor. This hypothesis is supported by preliminary results of a study, indicating that a mixture of two plasmids encoding gp100 and trp-2 increases the rate of protection in C57BL/6 mice from challenge with B16 melanoma cells.5
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Acknowledgments |
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FOOTNOTES |
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1 Supported in part by the Italian Association for
Cancer Research and by the Istituto Superiore Sanità Italy-USA
cooperative program for the therapy of cancer (Grant 981/A.14). E. A.
is supported by a fellowship from The Italian Foundation for Cancer
Research. 
2 To whom requests for reprints should be
addressed, at Department of Oncology and Surgical Sciences, Oncology
Section, University of Padova, Via Gattamelata 64, 35128 Padova, Italy.
E-mail: vbronte{at}ux1.unipd.it
3 The abbreviations used are: Ag, antigen; TRP,
tyrosinase-related protein; MDA, melanocyte lineage differentiation
antigen; rVV, recombinant vaccina virus; NK, natural killer; mAb,
monoclonal antibody; MLPC, mixed leukocyte peptide culture; PFU,
plaque-forming unit(s).
4 Internet address:
http://www.genweb.com/Dnavax/dnavax.html.
5 A. Singhal, G. Thai, N. Thull, N. Eslashi, M.
Matar, V. Bronte, and F. Pericle, manuscript in
preparation.
Received 8/27/99. Accepted 11/30/99.
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and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp. Med., 173: 647-658, 1991.This article has been cited by other articles:
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