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Divisions of Gynecologic Oncology [K. O., F. Q., J. T., B. K., S. L.], Pathology [M. I., A. B.], Biostatistics [D. D.], and Immunology [K. O., F. Q., A. S.], Roswell Park Cancer Institute, Buffalo, New York 14263; Weill Medical College of Cornell University, New York, New York 10021 [Y-T. C.]; Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [A. J., E. S., S. G., D. S., B. W., M. J. S., G. R., L. J. O.]
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INTRODUCTION |
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85%. Within 2 years of cytoreductive surgery and systemic chemotherapy, tumors usually reoccur, and once relapse occurs, there is no known curative therapy. Thus, there is a need to develop additional therapeutic approaches for the management of this disease. A proposed strategy for minimizing the risk of recurrent disease is immunotherapy. Patients who demonstrate complete response to frontline surgery and chemotherapy could be considered for immunotherapy, with the presumption that the majority do in fact have micrometastases. However, the development of successful immunotherapeutic strategies requires the identification and characterization of immunogenic ovarian cancer antigens that will be recognized by the host immune system, leading to tumor rejection. The development of approaches for analyzing humoral (3) and cellular (4) immune reactivity to cancer in the context of the autologous host has led to the molecular characterization of tumor antigens recognized by autologous CD8+ T cells (5) and/or antibodies (6) . As a consequence of these advances, human tumor antigens defined to date can be classified into one or more of the following categories: (a) differentiation antigens, e.g., tyrosinase (7) , melan-A/MART-1 (8 , 9) , and gp100 (10) ; (b) mutational antigens, e.g., CDK4 (11) , ß-catenin (12) , caspase-8 (13) , and P53 (14) ; (c) amplification antigens, e.g., Her2/neu (15) and P53 (16) ; (d) splice variant antigens, e.g., NY-CO-37/PDZ-45 (14) and ING1 (17) ; (e) viral antigens, e.g., human papillomavirus (18) and EBV (19) ; and (f) CT antigens, e.g., MAGE (20) , NY-ESO-1 (21) , and LAGE-1 (22) . The CT antigens are a distinct and unique class of differentiation antigens. The defining characteristics of these antigens are the high levels of expression in adult male germ cells, but generally not in other normal adult tissues, and aberrant expression in a variable proportion of a wide range of different cancer types.
To be considered for antigen-specific immunotherapy of any tumor type, including EOC, an ideal candidate antigen should not only demonstrate high frequency expression in the tumor tissues and restricted expression in normal tissues, but also evidence for inherent immunogenicity. With regard to CT antigens, NY-ESO-1, initially defined by serological analysis of recombinant cDNA expression libraries in esophageal cancer (23) , is particularly immunogenic, eliciting both cellular and humoral immune responses in a high proportion of patients with advanced NY-ESO-1-expressing tumors (24 , 25) . In contrast, cellular and humoral immune responses to other CT antigens appear to be less frequent. In the present study, we analyzed the expression pattern of NY-ESO-1 in a large number of EOC patients. We have also investigated the composite expression of LAGE-1, another CT antigen with 94% homology to NY-ESO-1 (22) . In addition, we examined the evolution of serum antibody titers to NY-ESO-1 and LAGE-1 over extended periods of time in patients with EOC. Our results show that a significant proportion of human EOCs express NY-ESO-1 and/or LAGE-1 tumor antigens. In addition, we demonstrate the presence of humoral immune response in a group of EOC patients with NY-ESO-1- and LAGE-1-expressing tumors. These findings suggest that the NY-ESO-1 and LAGE-1 CT antigens are promising candidates for cancer-specific immunotherapy in EOC.
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MATERIALS AND METHODS |
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Cell Lines.
Five ovarian cancer cell lines, SVOV3, OVCA-429, OVCA-432, SK-OV-3, and OVCAR-3, were purchased from the American Type Culture Collection and grown in the recommended media under standard conditions. The immortalized human normal ovarian surface epithelial cell lines, IOSE and HOSE, were gifts from Dr. Nancy Auersperg (University of British Columbia, Vancouver, BC) and Dr. Sam Mok (Harvard University, Boston, MA), respectively.
Total Tissue RNA Isolation.
Total tissue RNA was isolated from frozen tumor tissues and from ovarian cancer cell lines by use of the TRIReagent (Molecular Research Center Inc, Cincinnati, OH) according to the manufacturer’s protocol. Potentially contaminating DNA was removed by treating with RNase-free DNase I (Boehringer-Mannheim, Mannheim, Germany). After phenol treatment and drying, RNA was dissolved in RNase-free H2O. The resulting RNA concentration was measured spectrophotometrically (GeneQuant; Amersham Pharmacia Biotech Ltd., Cambridge, United Kingdom), and the quality of the RNAs was checked by electrophoresis on 1% agarose gel.
RT-PCR Analysis of NY-ESO-1 and LAGE-1 Expression.
Two micrograms of each RNA sample were subjected to cDNA synthesis using the Ready-To-Go first strand synthesis kit (Pharmacia, Uppsala, Sweden). PCR was subsequently performed to analyze expression of NY-ESO-1 and LAGE-1. The primers for NY-ESO-1 were ESO1A (5'-CACACAGGATCCATGGATGCTGCAGATGCGG-3') and ESO1B (5'-CACACAAAGCTTGGCTTAGCGCCTCTGCCCTG-3'), and the primers for LAGE-1 were LAGE1A (5'-CTGCGCAGGATGGAAGGTGCCCC-3') and LAGE-1B (5'-CACACAAAGCTTGGCTTAGCGCCTCTGCCCTG-3'). Amplification for both gene products was 1 min at 94°C, 1 min at 60°C, and 1.5 min at 72°C for 35 cycles. These cycles were followed by a 10-min elongation step at 72°C. Testicular tissue was used as a positive control. The PCR products were 341 and 338 bp for NY-ESO-1 and LAGE-1, respectively, and were visualized by ethidium bromide staining after separation over a 1.5% agarose gel.
IHC.
Tumor specimens were fixed with buffered formalin and embedded in paraffin. Sections (5 µm) were placed on glass slides, heated at 60°C for 20 min, and then deparaffinized with xylene and ethanol. For antigen retrieval, tumor specimens mounted on glass slides were immersed in preheated antigen retrieval solution (DAKO high pH solution; DAKO, Carpinteria, CA) for 20 min and allowed to cool for 20 min at room temperature. After the inactivation of endogenous peroxidase, mAb to NY-ESO-1 (clone ES121) was then added at a concentration of 2.5 µg/ml and incubated overnight at 4°C. ES121 has been described previously (27)
. The primary antibody was detected with a biotinylated antimouse IgG (DAKO). Diaminobenzidine tetrahydrochloride was then added for development for 10 min, followed by counterstaining with hematoxylin solution.
The extent of immunohistochemical reactivity was graded as follows: negative, focal, staining of single cells or small clusters of cells (approximately <5% cells stained); +, 5–25% of cells stained; ++, >25–50% of cells stained; +++, >50–75% of cells stained; and ++++, >75% of cells stained. Negative control slides omitting the primary antibody were included in all assays. At present, no mAb is available that distinguishes NY-ESO-1 and LAGE-1.
ELISA.
Recombinant NY-ESO-1 and LAGE-1 truncated proteins (25)
at a concentration of 1 µg/ml in coating buffer [15 mM Na2CO3, 30 mM NaHCO3 (pH 9.6), 0.02% NaN3] were adsorbed to 60 x 10 TC microwell plates (Nunc, Roskilde, Denmark) at 10 µl/well overnight at 4°C. Plates were washed with PBS and blocked overnight at 4°C with 10 µl/well of 2% BSA in PBS. After washing, 10 µl/well of serum dilutions in 2% BSA were added and incubated for 2 h at room temperature. Plates were washed, and 10 µl/well diluted secondary antibody-2% BSA were added (goat anti-human IgG-AP; Southern Biotechnology, Birmingham, AL) and incubated for 1 h at room temperature. Plates were washed, incubated with 10 µl/well of substrate solution (Attophose substrate; JBL Scientific, San Louis Obispo, CA) for 25 min at room temperature, and immediately read (Cyto-Fluor 2350; Millipore, Bedford, MA). Sera were tested over a range of 4-fold dilutions from 1:100 to 1:100,000, as described previously (25)
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Statistical Analysis.
All statistical analyses were performed with the SPSS software (28)
. Statistical correlations were calculated using Pearson’s r. The distributions of NY-ESO-1 and LAGE-1 expression and clinical outcome were analyzed by the 
2 test. Estimated survival distributions were calculated by the method of Kaplan and Meier (29)
, and tests of significance with respect to survival distributions were based on the log-rank test (30)
. No adjustments were made for multiple comparisons.
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RESULTS |
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. The median age of the study population was 61 years (range, 22–89 years), and the median duration of follow-up was 25 months (range, 1–126 months). As expected, the majority of patients presented with grade 3 tumors (88%), at stage IIIc (78%) and with serous histology (79%). A complete response to therapy was achieved in 97 of the 190 patients (51%), and a partial response was achieved in 81 patients (42%), whereas the remaining patients had no response. The median estimated overall survival for all patients was 55 months (CI, 38–71 months), whereas the median disease-free survival, excluding patients with persistent/progressive disease after initial therapy, was 33 months (CI, 23–42). The 5-year disease-free and overall survivals for the entire study population were 31% (CI, 18%–44%) and 46% (CI, 36%–56%), respectively.
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. The intensities of the PCR products were heterogeneous, and some specimens yielded only faint amplicon bands. These were scored positive only if the result could be reproduced by a repeated RNA extraction and specific RT-PCR from the same tumor specimen. Cases with very low transcript levels that were not reproducibly positive were not regarded as positive. The normal ovarian surface epithelial cell line, IOSE, expressed LAGE-1, whereas the HOSE cell line did not express either tumor antigen. Four of the five ovarian cancer cell lines tested (80%) were positive for one or both tumor antigens. The SK-OV-3 cell line demonstrated dual expression of NY-ESO-1 and LAGE-1, whereas SVOV-3 was negative for both antigens (Fig. 1
; Table 2
). NY-ESO-1 mRNA expression was detected in 32 of 107 (30%) and LAGE-1 mRNA expression in 22 of 107 (21%) tumors. Coexpression of NY-ESO-1 and LAGE-1 mRNA was demonstrated in 12 of 107 (11%) specimens. Overall, expression of either NY-ESO-1 or LAGE-1 mRNA was observed in 42 of 107 (40%) of EOC specimens (Table 3)
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, and the staining was restricted to germ cells. No reactivity in other structures of the testis was noted. The germ cells revealed nuclear and cytoplasmic staining that was typically strongest in the early cells of germ cell maturation. Positive staining was observed in 62 of 143 (43%) archival, formalin-fixed, paraffin-embedded ovarian cancer samples. Reactivity was mostly heterogeneous, i.e., present in discrete areas of the tumors (focal or "+" staining according to our grading). Panels b–f in Fig. 2
show examples of focal through homogeneous staining patterns. The predominant expression pattern was heterogeneous (focal, +, ++), occurring in 41 of 62 (66%) of NY-ESO-1-positive specimens, whereas the remaining 21 of 62 (34%) demonstrated +++ or +++ staining (Table 4)
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. In the subset of 62 tumor specimens cotyped for NY-ESO-1 by RT-PCR and IHC, there was a significant correlation between RT-PCR and IHC (r = 0.03). In 12 specimens, ES121 immunostaining was present in the absence of demonstrable mRNA expression by RT-PCR. All of these specimens revealed a restricted ES121 immunoreactivity (focal to ++ according to our IHC grading), some consisting of only single positive cells. No discrepancy between IHC and RT-PCR was observed in all of the tumor tissues with homogeneous (+++ or ++++) immunoreactivity. In nine tumor tissues, NY-ESO mRNA was present in the absence of ES121 immunoreactivity. These cases consistently showed weak bands by RT-PCR.
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, 4
, and 5
. Patients whose tumors expressed NY-ESO-1 by IHC and/or RT-PCR (Table 5)
had a median disease-free survival of 32 months (CI, 17–47 months) and a median overall survival of 54 months (CI, 29–80 months), compared with 32 (CI, 18–46) and 55 (CI, 40–70) months, respectively, among patients whose tumors did not express NY-ESO-1 (P = 0.74 and 0.97, respectively, for both comparisons). There was no statistically significant difference in the distribution of the expression of NY-ESO-1 and histological grade (P = 0.21). Although tissue expression of NY-ESO-1 was associated with a higher stage of disease (P = 0.005), the estimated 5-year disease-free survival rate was 30% (CI, 12%–48%) among patients whose tumors expressed NY-ESO-1 and 33% (CI, 11%–57%) among patients whose tumors did not express NY-ESO-1 (not significant; Fig. 3a
). The estimated 5-year overall survival rate was 47% (CI, 33%–61%) among patients whose tumors expressed NY-ESO-1 and 44% (CI, 30%–58%) among patients whose tumors did not express NY-ESO-1 (not significant; Fig. 3b
). There were no significant differences in survival distributions when patients were compared based on the degree of tissue immunoreactivity (P = 0.06; Table 4
).
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. When all patients with tissue expression of either NY-ESO-1 and/or LAGE-1 by RT-PCR and/or IHC were considered [i.e., 55 of 107 (51%)], no significant correlation was observed with stage, grade, histology, disease-free survival, or overall survival. Among the 97 patients who demonstrated complete response to front-line surgery and chemotherapy, 36 (37%) patients demonstrated tissue expression of NY-ESO-1 by RT-PCR and/or IHC. There were no significant differences in disease-free and overall survival when this group was stratified by NY-ESO-1 expression. A subset of 62 patients with complete response to front-line surgery and chemotherapy were compared by LAGE-1 mRNA expression. Again, no significant differences in disease-free and overall survival were noted between the groups.
Antibody Response to NY-ESO-1/LAGE-1 in Ovarian Cancer Patients.
A total of 171 serum samples from 48 patients were analyzed by ELISA for NY-ESO-1/LAGE-1 antibodies. These sera consisted of preoperative and serial specimens obtained during patients’ course of disease (range, 1–3 years). Because of the high degree of homology between the NY-ESO-1 and LAGE-1, the serological assay did not reliably distinguish NY-ESO-1 and LAGE-1 in human sera. Therefore, the antibody responses to both antigens were considered together. A demonstrable antibody response to NY-ESO-1/LAGE-1 was found in 12 (25%) of the patients. One patient developed NY-ESO-1/LAGE-1 antibody 7 months after diagnosis and remained positive 3 years after initial therapy. All of the remaining patients antibodies present at the time of diagnosis. Another NY-ESO-1/LAGE-1 antibody-positive patient at baseline became negative 1 year after frontline treatment. Subsequently, she developed recurrent disease after 4 months and again became NY-ESO-1 and LAGE-1 antibody positive. All NY-ESO-1 or LAGE-1 antibody-positive patients at baseline and with sera available at up to 3 years of follow-up continued to demonstrate the presence of antibody.
Correlation of Antibody Response to NY-ESO-1/LAGE-1 with Clinical Outcome.
Among the 48 patients tested by ELISA, 37 had NY-ESO-1/LAGE-1-expressing tumors (by RT-PCR and/or IHC). NY-ESO-1/LAGE-1 antibody was present in 11 of 37 (30%) EOC patients with NY-ESO-1/LAGE-1-expressing tumors. Only one patient whose tumor did not express NY-ESO-1 or LAGE-1 had demonstrable antibody to NY-ESO-1/LAGE-1. The analysis of clinical outcome comparing the 11 NY-ESO-1/LAGE-1 antibody-positive with the 27 antibody-negative patients with NY-ESO-1/LAGE-1-expressing tumors showed no significant differences in disease-free and overall survival. The detailed characteristics of the 12 patients with demonstrable NY-ESO-1/LAGE-1 antibody are shown in Table 6
. All of the patients had tumors of serous histology (except one patient with transitional cell carcinoma) and advanced stage (11 with stage IIIC, 1 with stage IV disease). The analysis of serum samples obtained at 3 years on all eight patients with extended follow-up, including patients who remained disease-free after initial therapy, demonstrated the presence of NY-ESO-1/LAGE-1 antibody.
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DISCUSSION |
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50% showed expression of at least one of these two CT antigens. These findings suggest that NY-ESO-1 and LAGE-1 might represent targets for immunotherapy in a significant proportion of patients with EOC. In an effort to determine the inherent immunogenicity of NY-ESO-1 and LAGE-1 in patients with EOC, we studied a subset of 48 patients for whom tumor and serum specimens from the same patients were available. We compared the NY-ESO-1 and LAGE-1 antibody status with mRNA and/or protein expression in the autologous tumor. The results showed that NY-ESO-1/LAGE-1 antibodies were present in 30% of patients with NY-ESO-1- and LAGE-1-positive tumors, and only one patient with an NY-ESO-1- and LAGE-1-negative tumor had NY-ESO-1 antibody. In a survey of sera from normal individuals and cancer patients, Stockert et al. (25) reported the presence of antibodies to NY-ESO-1 in 40–50% of patients with advanced NY-ESO-1-expressing tumors, and no patients with NY-ESO-1-negative tumors had NY-ESO-1 antibody. Although the reported frequency of antibody response was only 12.5% in ovarian cancer patients in the study (25) , the tumor NY-ESO-1/LAGE-1 antigen phenotype was not known.
Our demonstration of humoral immune response in a significant proportion of EOC patients with NY-ESO-1/LAGE-1-expressing tumors is consistent with the known immunogenicity of these antigens and the biology of EOC. This is particularly relevant in light of previous reports demonstrating that a humoral immune response to NY-ESO-1 was predictive of a strong CD8+ T-cell response to NY-ESO-1-derived peptides, as measured by tetramer, enzyme-linked immunospot, and cytotoxicity analyses (34) . Of interest is our finding of a spontaneous humoral immune response persisting for several years in EOC patients with no apparent evidence of disease. Although it is possible that long-lasting spontaneous immunity to NY-ESO-1/LAGE-1 can occur in tumor-free individuals, an alternative hypothesis is that these patients continue to have micrometastatic disease that provides the antigenic stimulus for the immune system. This latter explanation is particularly appealing because the vast majority of patients with EOC will ultimately have recurrences, and previous reports indicate that the humoral immune response to NY-ESO-1 is antigen driven (25) .
Previous studies have shown that patients with NY-ESO-1 antigen expression and antibody tend to have advanced-stage cancer. For example, a higher frequency of NY-ESO-1 expression in bladder cancer was correlated with high nuclear grade (35)
, and NY-ESO-1 antibody response was correlated with advanced stage of disease (25
, 36)
. In our present study of a large set of EOC patients, the lack of correlation of NY-ESO-1 and LAGE-1 antigen expression with clinicopathological characteristics (histological type, tumor grade, recurrence, and survival) may reflect the fact that 96% of the patients (Table 1)
had advanced stage disease. In a recent study of patients with early stage EOC, low frequencies of NY-ESO-1 expression were detected,4
suggesting that the expression of NY-ESO-1 also correlates with advanced stage EOC. This raises important questions about the role of CT antigens in tumorigenesis, invasion and metastasis in EOC. First, what are the functions of these CT antigens? Second, at what stage in the malignant process does CT antigen expression become evident? Third, given the immunogenicity of some the CT antigens (e.g., NY-ESO-1), does the presence of detectable spontaneous immune response correlate with better clinical outcome? Fourth, will the induction and/or augmentation of CT antigen-specific immunity by immunotherapy likely to be associated with clinical benefit? Because of the small number of patients with spontaneous immunity to NY-ESO-1 in the present study, it is not possible to make a definitive statement about the prognostic significance of NY-ESO-1 immunity in EOC.
Even if the expression of CT antigens in tumors represents only an epiphenomenon rather than playing a clearly defined role in tumor progression in EOC, CT antigens still represent attractive targets for immunotherapy because of their tissue-restricted expression and immunogenicity. For example, in a recent Phase 1 clinical trial, 12 HLA-A2+ patients with progressing NY-ESO-1-expressing metastatic tumors of different types were vaccinated intradermally with NY-ESO-1 peptides first alone and then in combination with granulocyte-macrophage colony-stimulating factor as a systemic adjuvant (37) . In five of seven vaccinated patients who were initially NY-ESO-1 antibody negative, individual metastases stabilized or regressed after induction of NY-ESO-1-specific CD8+ T-cell responses. In addition, there was disease stabilization after NY-ESO-1 immunization in three of five antibody-positive patients, indicating that vaccination may also yield clinical benefit in patients with baseline spontaneous immunity to NY-ESO-1.
We conclude that NY-ESO-1 and LAGE-1 antigens meet the criteria for inclusion as targets for active specific immunotherapy in EOC. These criteria include (a) demonstration that the tumor antigen is expressed at a reasonable frequency in tumors, (b) demonstration of restricted or no expression in other normal tissues, and (c) demonstration of immunogenicity. On the basis of these considerations, we have initiated a clinical trial of antigen-specific immunotherapy in EOC, using these target CT antigens. However, the fact that NY-ESO-1 and LAGE-1 are expressed in only a fraction of EOC underlines the need for identifying other antigens in this disease that could serve as targets for immunotherapy. In this regard, we have continued the analysis of additional CT antigens in EOC and initiated a comprehensive "immunomic" analysis (38) of EOC to uncover additional antigenic targets for polyvalent vaccine development.
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FOOTNOTES |
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1 Supported by a Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative Grant. 
2 To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021. Phone: (212) 450-1500; Fax: (212) 450-1555; E-mail: lold{at}licr.org
3 The abbreviations used are: EOC, epithelial ovarian cancer; CT, cancer-testis; RT-PCR, reverse transcription-PCR; IHC, immunohistochemistry; mAb, monoclonal antibody; CI, confidence interval.
4 A. A. Jungbluth, personal communication.
Received 5/16/03. Revised 6/23/03. Accepted 6/26/03.
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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 |
