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Immunology |
Johannes Gutenberg Universität, III. Medizinische Klinik, 55131 Mainz [B. S., U. W., C. H.]; Deutsches Krebsforschungsinstitut, 69720 Heidelberg [F. M.]; and Max Delbrück Centrum für Molekulare Medizin, 13122 Berlin, [T. B.] Germany
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and -ß, and the chaperone tapasin. In contrast, calnexin,
calreticulin, ER60, and protein disulfide isomerase expression
are unaltered or only marginally suppressed in these cells. The level
of down-regulation of the components of the antigen-processing pathway
is either transcriptionally or posttranscriptionally controlled and
could be corrected in all cases by IFN-
treatment, which also
reconstituted MHC class I surface expression. Thus, B16 melanoma cells
can be used as a model for the characterization of the mechanisms
underlying the coordinated dysregulation of the antigen-processing
components, which should provide new insights into the development of
tumors and the factors controlling this process. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although B16 melanoma cells fail to induce strong T cell-mediated immune responses, some B16 melanoma antigen-specific T cells have also been described (8 , 9) . Adoptively transferred surrogate marker OVA-specific CD8+ T cell populations in mice bearing established OVA-transfected B16 melanoma lung metastases mediate a reduction of tumor growth and, subsequently, a prolonged survival (10) . In addition, the poorly immunogenic phenotype of B16 cells could be altered by the fusion of dendritic cells with syngeneic B16 melanoma cells (11) .
Despite these reports, the use of the H-2-deficient B16 melanoma model
as a prototype for T cell-based immunotherapies independent of
cross-priming has to be reconsidered (12)
. Abnormalities
of MHC class I surface antigens are often associated with an immune
escape of tumor cells. The reduction or loss of MHC class I surface
expression in human and murine tumors of distinct histologies could be
attributable to structural alterations and/or dysregulation of various
components of the MHC class I APM (13, 14, 15, 16)
. The
complexity of the MHC class I antigen pathway has been well defined in
the last decade. The pathway includes four major components:
(a) the multicatalytic proteasome, in particular the LMPs 2,
7, and 10, and its PAs, PA28 and -ß; (b) TAP;
(c) numerous chaperones; and (d) the MHC class I
molecules (17, 18, 19, 20, 21, 22)
. Deficient expression of LMP, PA28, and
TAP alters both the quality and/or quantity of the peptide repertoire
presented in the context of MHC class I molecules (19)
. In
addition, down-regulated or a lack of tapasin expression also affects
MHC class I expression (23
, 24)
.
The underlying mechanism of the impaired MHC class I surface expression
in B16 melanoma cells has not yet been identified. We now present
evidence that the deficient H-2 expression of B16 melanoma cells is
attributable to a coordinate suppression of multiple components of the
MHC class I APM. These defects could be corrected by IFN-
administration, which transcriptionally induces the expression of
various APM components, thereby also enhancing MHC class I surface
expression in B16 cells. Thus, our data have important implications for
the use of the B16 melanoma model in immunotherapeutical studies and
the interpretation of their results as well as for the identification
of the underlying mechanisms of the impaired expression of the
antigen-processing genes.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment. stimulation, tumor cells were incubated in the presence of 20
ng/ml murine recombinant IFN- (Roche Diagnostics, Mannheim, Germany)
for 24–48 h at 37°C (26)
.
Flow Cytometry.
The mAbs used in this study were antimouse
H-2KbDb (Cedarlane, Hornby,
Canada) and the FITC-conjugated goat antimouse immunoglobulin
(Beckman/Coulter, Krefeld, Germany) as the secondary mAb. For staining
of MHC class I antigens, cells were incubated with the primary mAb for
30 min on ice, washed twice in PBS and incubated further with a
FITC-conjugated goat antimouse immunoglobulin (Coulter/Beckman,
Krefeld, Germany) as a secondary mAb for an additional 30 min.
After washing in PBS/1% heat-inactivated FCS, cells were analyzed on a
flow cytometer (Coulter Epics XL MCL; Beckman/Coulter, Krefeld,
Germany).
MHC Class I Stability Assays.
Peptide-binding assays were performed using the
H-2Kb restricted peptide SIINFEKL (OVA pos
257–264) and the human HLA-A2-restricted nonsense peptide (HIV pos
476–484), as described recently by Wölfel et al.
(27)
. Briefly, 3 x 105 cells/well were incubated for 16 h in
serum-free RPMI 1640 (Biochrom, Berlin, Germany) in the presence or
absence of the respective peptides (100 µM,
dissolved in PBS containing 5% DMSO) with or without 2.5 µg/ml human
ß2-microglobulin (Sigma, Deisenhofen,
Germany), before MHC class I surface expression was determined by flow
cytometry.
Stable Transfection.
The TAP1 and TAP2 expression
vectors4
carrying the human TAP1 or TAP2 cDNA, respectively, under the control
of the cytomegalo virus-promoter and the
neoR gene as a selection marker, as well
as the control vector P46 carrying the
neoR gene alone, were used for stable gene
transfers. Transfections were performed with 2.5 x 106 cells in a volume of 500 µl of MEM
containing 1% heat-inactivated FCS and 10 µg of linearized plasmid
DNA using electroporation (450V, 1200 µF, 2 µs; EPI
2500; Fischer, Heidelberg, Germany). After pulsing, the cells were
plated in complete medium on Petri dishes and 48 h later,
neoR cells were selected in complete RPMI 1640
containing 600 µg/ml G418 (Seromed, Berlin, Germany). Four weeks
later, neoR cells were analyzed for the
expression of the transgene as well as for MHC class I surface
antigens.
RT-PCR Analysis.
All oligonucleotides used for PCR amplifications were purchased from
Biometra (Göttingen, Germany) and are listed in Table 1
. For conventional RT-PCR analysis, reverse transcription was performed
using 1 µg of total cellular RNA extracted by guanidinium
isothiocyanate/cesium chloride preparation (28)
in 22-µl
reaction volume in the presence of a hexanucleotide mixture (Roche
Diagnostics, Mannheim, Germany) and 10 units of Moloney leukemia virus
reverse transcriptase (United States Biochemical, Cleveland, OH). For
amplification, 2-µl aliquots of cDNA were used as a template in 50
µl of reaction buffer containing the respective concentration (pmol)
of each primer, 1.5 mM MgCl2, 200
µM deoxynucleotide triphosphate (Perkin-Elmer,
Weiterstadt, Germany), the appropriate amount of 10x PCR-buffer (Roche
Diagnostics, Mannheim, Germany), and 1.5 units Taq DNA Polymerase
(Roche Diagnostics, Mannheim, Germany) or Ampli-Taq-Gold
(Perkin-Elmer). One-step PCR was performed as described recently
(29)
using 200 ng of total RNA. The cDNA amplifications
were performed with multiple primer sets in a thermocycler (Biometra,
Göttingen, Germany) with 24–35 cycles of denaturation (1 min;
95°C), specific annealing (1 min; 56°C-63°C), and
elongation (1 min, 72°C). The amplification products were separated
on 1–2% agarose gels, stained with ethidium bromide, and photographed
under UV light. Specificity of amplification reactions was confirmed by
Southern blot.
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(1:2000), and antimouse PA28ß mAb (1:1000; Affinity, Exeter,
United Kingdom) at 4°C overnight and then incubated with horseradish
peroxidase goat antirabbit immunoglobulin (1:1250; DAKO,
Hamburg, Germany) for 60 min at room temperature. Filters were
then processed using the chemiluminescence kit (ECL; Amersham,
Braunschweig, Germany) and exposed to X-OMAT Blue films (Kodak,
Rochester, NY). The experiments were performed at least twice.
Peptide Translocation Assay.
Cells (2.5 x 106) per
incubation were harvested and washed with the incubation buffer
[130 mM KCl, 10 mM NaCl, 1 mM
CaCl2, 2 mM EGTA, 2 mM
MgCl2, and 5 mM HEPES (pH 7.3); Ref.
30
]. Cells were permeabilized with 2 IU streptolysin
O/ml (Welcome Reagent Ltd., Beckenham, United Kingdom) in 50
µl of incubation buffer for 10 min at 37°C before the addition of
10 µl ATP (10 mM; La Roche Diagnostics,
Mannheim, Germany), 2.5 µl of radioiodinated model peptides (peptide
no. 63, RYWANATRSI; peptide no. 67, RYWANATRSF; and peptide no. 600,
TNKTRIDGQY) and incubation buffer to a final volume of 100 µl.
Peptide translocation was performed routinely for 15 min at 37°C. The
permeabilized cells were lysed with 1 ml of NP-40 lysis mix. The
glycosylated peptides within the endoplasmic reticulum were
recovered with ConA-Sepharose (Pharmacia, Uppsala, Sweden) as described
previously (30)
.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These data suggest that decreased levels of MHC class I surface
antigens in B16 melanoma cells appear to be caused not only by an
impaired peptide supply in the endoplasmic reticulum but rather to be
attributable to a more complex process.
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and -ß,
the peptide transporter TAP1, and tapasin in both B16 subclones when
compared with RMA control cells (Fig. 1A)
. Interestingly, the steady-state mRNA levels of TAP2,
calnexin, calreticulin, ER60, and protein disulfide isomerase were
either unaltered or only marginally down-regulated in both B16 cell
lines (Fig. 1A
; data not shown).
|
and -ß (Fig. 1B)
. The results
also suggest a differential regulation of the various APM
components. The presence of normal levels of TAP2 mRNA (Fig. 1A)
coupled with low TAP2 protein levels (Fig. 1B)
appears to be attributable to either
posttranscriptional down-regulation, a decrease in TAP2 translation, or
TAP2 protein stability. In contrast, the lack of or low levels of
steady-state mRNA and proteins for the other APM components, such as
TAP1, tapasin, the LMP subunits, and PA28, may account for the
transcriptional control of these components.
To examine whether the impaired TAP expression in B16 cells was
directly associated with a strong suppression of the peptide transport
rate, peptide translocation assays were performed. Streptolysin
O-permeabilized B16 cells and respective controls (RMA,
RMA-S, and Renca) were incubated in the presence and absence of ATP
with three different iodinated model peptides (nos. 63, 67, and 600)
carrying a glycosylation sequence, respectively. As demonstrated
representatively in Fig. 2
, for the peptides no. 63 and no. 67, TAP function was nearly totally
inhibited in the B16 subclones in the absence and presence of ATP. As
expected, similar results were obtained for the TAP2-deficient RMA-S
cells (data not shown). In contrast, Renca cells used as positive
controls showed high levels of peptide transport in the presence of ATP
(Fig. 2)
, which was comparable with that of RMA cells (data not shown).
Similar results were obtained in translocation assays using peptide no.
600 (data not shown).
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-mediated Restoration of MHC Class I Surface Expression
Attributable to Increase of the Expression of APM Components. was able to revert the deficient
expression of MHC class I APM genes, the steady-state mRNA
and protein levels of the various APM components in the two B16
subclones were analyzed after 24 and 48 h of IFN- treatment,
respectively. As shown in Fig. 1
, the mRNA and protein expression of
the peptide transporter, the LMP subunits, the PAs, and/or tapasin was
stimulated in the B16F1 and B16 F10 cell lines upon IFN-
administration. The IFN--mediated induction of these APM components
was accompanied by an increase in MHC class I surface expression in
both B16 subclones and in RMA and Renca cells but not in TAP2-deficient
RMA-S cells (Table 1)
.
No Correction of MHC Class I Surface Expression by
TAP Gene Transfer into B16 Cells.
To investigate whether TAP down-regulation is the major component
affecting the MHC class I surface expression, TAP1 or
TAP2 genes alone and in combination were stably introduced
into both B16 melanoma subclones. After selection in G-418,
neoR clones were analyzed for integration and
expression of the transgenes by genomic and RT-PCR analysis,
respectively. All neoR B16 transfectants showed
both integration and expression of the TAP subunits. However, flow
cytometry revealed that overexpression of TAP1 and TAP2 alone or in
combination was not accompanied by an induction of H-2 antigen
expression (data not shown). Because the impaired expression of MHC
class I antigens could not be reconstituted by TAP gene
transfer, the coordinated down-regulation of multiple APM components
seems to account for the deficient levels of MHC class I antigens on
B16 melanoma cells and their immune escape phenotype. The underlying
mechanisms of such concordant dysregulation of APM components still
have to be elucidated.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A coordinated suppression of LMP, PA28, TAP, tapasin, and MHC
class I heavy chain was observed in the B16 subclones (Fig. 1
, Table 2
), but both the extent as well as the level of down-regulation of
these components appear to be distinct. With the exception of TAP2 and
a number of chaperones, low levels of steady-state mRNA as well as
protein was found for various APM components. Transcriptional
down-regulation or low mRNA stability may account for this defect. In
contrast, the normal levels of TAP2 mRNA associated with low TAP2
protein levels may be attributable to a posttranscriptional or
translational down-regulation or may occur at the posttranslational
level (Fig. 1)
.
The simultaneous down-regulation involved genes not only clustered in the MHC class II locus, suggesting a general mechanism of APM-component suppression in the B16 melanoma system. Thus, the B16 melanoma model serves as an example of how tumor cells can and do avoid the host immune system. These results are in accordance with those of Johnsen et al., (32) demonstrating an impaired expression of various APM molecules in tumors of distinct origin. On the other hand, these data are in contrast with oncogene- and virus-transformed murine fibroblasts, in which a concordant lack of a few specific APM components was described, whereas the expression of other APM genes was only marginally affected or unaltered (23 , 26 , 31) . Because of the extensive defects in the B16 system, more than known previously, the generation of T-cell responses may require either the repair of the dysfunctional mechanisms, which is difficult unless the precise lesion(s) is (are) identified, or cross-priming (12) .
The underlying mechanisms of the described concordant dysregulation of APM components in B16 cells still have to be elucidated. The immune escape phenotype of B16 cells could be abolished by cytokine treatment, but not by gene transfer of one of the major APM components, the peptide transporter TAP (data not shown), as it has been shown for human tumor cells (33, 34, 35, 36) . Because the decreased expression of proteasome subunits is not likely to decrease MHC class I expression (15) , one might speculate that the defect described in B16 subclones is attributable to impaired tapasin expression.
Because of the IFN--mediated induction of APM components in B16
cells, the deficient expression of these genes appears to be
attributable to regulatory mechanisms rather than to structural
alterations (Fig. 1
; Table 2
). At least for TAP1 and LMP2, a concordant
expression has been implemented in both human and murine cells because
of a shared bidirectional promoter (37)
. Although the
TAP1/LMP2, LMP7, LMP10, and PA28 promoters contain different
elements, the observed simultaneous down-regulation of these APM
components argues for a common regulatory mechanism in B16 melanoma
cells, which is presently under investigation. In addition to the
IFN--mediated stimulation of various APM components, MHC class I
surface expression was also increased upon IFN- treatment of B16
subclones, but to a lesser extent (Table 2)
. These data suggest that
additional regulatory factors, which are important for efficient MHC
class I antigen processing and presentation, may exist. This
hypothesis is also strengthened (1)
by the fact that the
MHC class I surface expression of B16 subclones could be enhanced by
neither the incubation of cells at low temperatures nor by the addition
of exogeneous MHC class I-binding peptides (Table 2
; Ref.
2
) and by the partial reconstitution of the MHC class I
surface expression in adenovirus 12-transformed fibroblasts
after the gene transfer of deficient APM components (31)
.
In addition, the induction of APM component expression upon IFN-
treatment may affect the H-2-deficient phenotype of B16 cells by
altering the quality and quantity of generated antigenic peptides.
Immunization with B16 cells stably transfected with the
IFN- gene alone, or particularly in combination with
H-2 genes, induced cytotoxic T-cell responses, a longer
survival, and a significant inhibition of metastasis formation
(5
, 6
, 38)
. However, these CD8+
cytotoxic T lymphocytes may not be directed solely against the peptide
repertoire presented by unmodified B16 cells.
Because of the extensive defects, more than known previously, T
cell-based immunotherapy in the B16 system is much more difficult than
expected. The generation of T-cell responses and an effective antitumor
immunity may require the correction of the underlying dysfunction,
e.g., by IFN-. Thus, given the presence of the
deficiencies in the antigen-processing pathway, the B16 melanoma cells
should not be used as a prototype for vaccination and immunization
strategies, or, at least, investigators using this model must
be aware of its demanding nature. A complete understanding of the
processes involved in APM suppression of B16 cells will provide new
insights into the molecular mechanisms of immune escape as well as into
the possibilities of how to repair those pathways. In this respect, B16
melanoma cells represent an excellent model system to study the
regulation of APM components, to identify new factors involved in this
process, and to optimize the effectivity of immunotherapy in correcting
these defects.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from the
Sonderforschungbereich 311 and 432 projects C8 and A5. 
2 To whom requests for reprints should be
addressed, at Johannes Gutenberg University, III. Department of
Internal Medicine, Langenbeckstr. 1, 55131 Mainz, Germany. Phone:
0049-6131-176760; Fax: 0049-6131-176678; E-mail: B.Seliger{at}3-med.klinik.uni-mainz.de
3 Abbreviations used are: mAb, monoclonal
antibody; APM, antigen-processing machinery; OVA, ovalbumin;
LMP, low molecular weight protein; neoR, neomycin
resistance; RT-PCR, reverse transcription-PCR; PA, proteasome
activator; TAP, transporter associated with antigen processing.
4 Jung and Seliger, unpublished observations.
Received 4/19/00. Accepted 11/29/00.
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| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
