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Clinical Cancer Research Vol. 9, 4159-4164, September 15, 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Major Histocompatibility Antigens and Antigen-processing Molecules in Uveal Melanoma1

Subramanian Krishnakumar, Dhiraj Abhyankar, Amirtha Lakshmi Sundaram, Vaijayanthi Pushparaj, Mahesh Palanivelu Shanmugam and Jyotirmay Biswas2

Department of Ocular Pathology [S. K., A. L. S., V. P., J. B.] and Ocular Oncology [M. P. S.], Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, 600 600, India, and Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 142631 [D. A.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Malignant transformation of cells is frequently associated with abnormalities in the human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with T cells and natural killer cells. Uveal melanoma is a highly malignant tumor of the eye and is characterized by hematogenic spread to liver. Antigen-processing molecules (APMs) are necessary for efficient expression of HLA class I antigens. We studied the expression of HLA antigens and the APM in uveal melanomas by immunohistochemistry and correlated clinicopathologically.

Experimental Design: HLA class I antigen, ß2-microglobulin (ß2-m), HLA class II antigens, and the APM comprising proteasomal subunits low molecular mass polypeptide (LMP) 2, ß-subunit of LMP2-{Delta}, LMP 10, transporter associated protein 1 subunit, and chaperone molecules tapasin and calnexin were studied in 41 primary uveal melanoma archival specimens by immunohistochemistry. Immunoanalysis was done by a semiquantitative method and correlated with extrascleral extension, cell types, and the largest tumor diameter.

Results: HLA class I antigen, ß2-m, HLA class II antigen, and the APM were decreased (negative staining in 29 tumors and dull staining in 3 tumors) in 100% (32 of 32) uveal melanomas with no extrascleral extension. (P = 0.01) and positive (bright staining) in 67% (4 of 9) tumors with liver metastasis. Decreased immunoexpression of HLA antigens and the APM was seen in nonepithelioid cell melanomas. There was no correlation with largest tumor diameter.

Conclusions: Our data suggest decreased expression of HLA, and APM are seen in uveal melanomas with no extrascleral extension and in nonepithelioid cell melanomas. Decreased expression of APM may contribute to decreased HLA class I antigen expression.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Uveal melanoma is the commonest primary intraocular tumor in Caucasian adults, with an incidence rate of 0.7/100,000. The average survival rate after the diagnosis of metastatic disease, usually in the liver, is between 2 and 7 months. No effective treatment for metastatic disease is yet available (1) . The therapy of uveal melanoma remains problematic because of the high rate of metastatic dissemination, irrespective of the success of treatment of the primary tumor. When metastatic disease is diagnosed, patient survival is usually <1 year (2) . Immunotherapy has generated a lot of interest in the treatment of metastatic uveal melanomas. MHC and the APM3 have generated interest in immunotherapy in many tumors (3) .

In uveal melanomas, abnormalities in the HLA class I antigen, ß2-m, and HLA class II antigens have been reported (4, 5, 6) . The pathway of APM involved in the generation of HLA class I molecule has been well defined recently. These include the low molecular proteasomal complexes, generating antigenic peptide fragments comprising of LMP 2, ß subunit of LMP2, i.e., {Delta}, LMP 7, and the recently described multicatalytic endopeptidase complex-like-1, also referred to as LMP10. LMP10 is not encoded in the MHC locus in contrast to LMP2 and LMP7. LMP10 is necessary for the expression of LMP 2. The new proteasomal {Delta}is highly homologous to LMP2 and expressed in a reciprocal manner with LMP2.

The transporter proteins TAP1, TAP2 translocate peptides from the cytosol to the ER. Different ER-resident chaperones calnexin, calreticulin, the binding protein tapasin, stabilize MHC class I molecules during their folding and/or assembly in the ER or assist their loading with peptides. Binding of high affinity peptides to MHC class I molecules leads to the dissociation of this TAP complex and the exit of the ternary MHC class I/ß2-m/peptide complex from the ER through the golgi for presentation to CD8+ CTLs. Deficiency of LMP, TAP, and the chaperone proteins reduces the supply and repertoire of peptides available for binding to MHC-1 (7, 8, 9) .

In contrast to a number of studies (4, 5, 6) demonstrating HLA class I antigen down-regulation in primary uveal melanoma lesions with favorable outcomes, there is little information about the expression of APM, which are responsible for generating peptides and efficient expression of HLA class I antigens. Therefore, in this present study, we investigated the immunoreactivity of HLA class I antigen, ß2-m, HLA class II antigen, and APM comprising proteasomal subunits LMP2, ß subunit of LMP2, i.e. {Delta}, LMP10, transporter protein TAP1 subunit, and chaperone molecules tapasin and calnexin and correlated with extrascleral invasion, cell types, and LTD in uveal melanomas.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient.
We had earlier published a large series on uveal melanomas among the Asian-Indians (10) . Forty-one uveal melanoma lesions were obtained from 29 male and 12 female patients with a median age of 45 years. All of the patients were evaluated at the ocular oncology clinic of our hospital between 1996 and 2000. Thirty-two were choroidal melanomas, 8 involved both the ciliary body and the choroid, and 1 was a diffuse uveal melanoma, which simulated metastatic tumor (11) .

The tumors were divided into two groups. Group A (no extrascleral extension) had 32 tumors, and group B (extrascleral extension/liver metastasis) had 9 tumors (5 tumors had extrascleral extension, and 4 tumors had both extrascleral extension and liver metastasis; communications received from the relatives of the patients, and they all had liver metastasis according to their family physicians). The follow-up data available from the medical records of all of the patients are given in Tables 1Citation and 2Citation . The minimum follow-up was for 6 months, and the maximum follow-up was for 60 months.


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  		Table 1 HLA antigen and APMs immunoreactivity in Group A uveal melanomas with no extrascleral extensiona

 

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  		Table 2 HLA antigen and APMs immunoreactivity in Group B uveal melanomas with extrascleral extension/liver metastasis

 
Inclusion and Exclusion Criteria.
Inclusion criterion was that all of the patients were treated by enucleation. Exclusion criteria included patients who had received pre or intraoperative adjunctive treatments, such as radiotherapy and cryotherapy. Melanomas with extensive necrosis and orbital cellulites were excluded (12) . Iris melanoma and metastatic melanomas to the uveal tract were excluded.

Tumor Samples.
Neoplastic tissues were obtained from enucleation material of the patients. Each sample was processed for conventional histopathological diagnosis. Histological sections were prepared from tissues fixed in 10% buffered neutral formalin for 48 h and embedded in paraffin. H&E-stained 6-µm sections were prepared through the central region of the tumor and reviewed for cell type, LTD, and extension of the tumor. The blocks were from consecutive patients.

Cell Type.
The designation of the cell type was based on the Callenders’ classification (13) . There were 17 spindle cell melanomas, 12 mixed cell melanomas, and 12 epithelioid cell melanomas. For the analysis, in this report, they were simplified into two groups as epithelioid and nonepithelioid melanomas comprising mixed and spindle cell melanomas, and the immunoreactiviity of the HLA antigens and the APM was assessed in these.

Tumor Size.
Tumor size was measured as the LTD in millimeters from histological sections under the microscope (14) . Tumors were divided into two groups according to the dimension, LTD <= 10 mm and LTD > 10 mm, and immunoreactivity was assessed in these two groups.

Monoclonal Antibodies.
The affinity purified mouse antihuman locus specific mAb HC-10 which recognizes HLA class I antigens, the anti-ß2-m mAb L368, the anti-HLA class II mAb LGII-612.14, and the molecules of the APM comprising anti-LMP2 mAb SY-1, anti-{Delta} mAb SY-4, anti-LMP10 mAb TO-6, anti-TAP1 mAb TO-1, anti-Tapasin mAb TO-4, and anti-Calnexin mAb TO-5, which were used, are target specific and exhibit no cross-reactivity (15) . The antibodies were gifts from Dr. Soldano Ferrone, Department of Immunology, Roswell Park Cancer Institute (Buffalo, NY). Labeled streptavidin kit was purchased from DAKO Laboratories (Glostrup, Denmark).

Immunohistochemistry.
Immunostaining of tissue sections was performed using labeled streptavidin by indirect immunoperoxidase technique. Briefly, 4-µm formalin-fixed paraffin sections were used for the study. Tissue sections were then deparaffinised and rehydrated and bleached before immunohistochemical procedure. Endogenous peroxidase was blocked with hydrogen peroxide for 10 min at room temperature. No antigen retrieval was performed before antibody incubation. Tissue sections were then rinsed in Tris-buffered saline (pH 7.6) and incubated with respective primary antibody for 1 h. This was followed by sequential 40-min incubation with biotinylated secondary antibody and streptavidin labeled to horseradish peroxidase (DAKO). Sections were washed with Tris-buffered saline between incubation. The peroxidase reaction was developed for 5 min using commercially available 3,3 'diaminobenzidine and counterstained with Harris hematoxylin.

Assessment of Immunohistochemical Results.
Tissue sections were read independently by two ocular pathologists (S. K. and J. B.) without the knowledge of the results obtained by the other investigator. Furthermore, each investigator read all of the slides twice without the knowledge of the results obtained in the previous reading. The staining intensity was scored as - (absent), +/- (dull), and + (bright). The tumors were graded as follows: positive (>75% cells stained and with bright intensity of staining), heterogeneous (25–75% of the cells stained, mainly at a dull intensity), with the percentage of cells expressed to nearest 10%), and negative (absent staining; HLA expression in cancer. International Histocompatibility Working Group, Project description).4

Variations in the percentage of stained cells enumerated by the two investigators were within a 10% range. The staining intensity of adjacent normal structures (i.e., lymphoid and endothelial cells) was used as an internal control to evaluate the staining intensity of malignant cells. For negative control, the primary antibody was omitted, and nonimmune serum was used in the immunostaining.

The study was reviewed and approved by the local ethics committee of our institute, and the committee deemed that it conformed to the generally accepted principles of research, in accordance with the Helsinki Declaration.

Statistical Analysis.
For statistical analysis, decreased expression (negative and heterogeneous) of HLA antigen and APM expression were compared with the positive expression in the tumors with no extrascleral extension (group A) and tumors with extrascleral extension and liver metastasis (group B). The immunoreactivity was also analyzed in the epithelioid and nonepithelioid melanomas and in tumors with LTD <= 10 mm and LTD > 10 mm using Fisher’s exact test.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The results of immunoperoxidase staining of HLA class I antigen, ß2-m and HLA class II antigen, and APM in groups A (with no extrascleral extension) and B (extrascleral extension) are shown in Tables 1Citation and 2Citation . Examples of a negative immunostaining of HLA class I antigen in spindle melanoma and positive immunostaining in melanoma with poor outcome are shown in Fig. 1, A and BCitation , respectively. The immunoexpression of HLA antigens and the APMs were concordant in the majority of the tumors.



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  		Fig. 1. A, negative immunostaining of HLA class I antigen in spindle cell uveal melanoma. B, positive immunostaining of HLA class I antigen in uveal melanoma with poor outcome (x20 objective).

 
Immunoreactivity of HLA Class I Antigens and ß2-m in Uveal Melanomas.
HLA class I antigen and ß2-m are decreased in 32 tumors (negative staining in 26 tumors and heterogeneous with 30–40% cells stained dull in six tumors) in group A with no extrascleral extension (Table 1)Citation . Among the 9 tumors in group B with extrascleral extension, HLA class I antigen and ß2-m are positive (bright staining in 80% cells) in 4 tumors with liver metastasis and decreased in 5 tumors (heterogeneous with 30% cells stained dull in 2 tumors and negative in 3 tumors) with no liver metastasis shown in Table 2Citation . The decreased expression of HLA class I antigen, ß2-m in the uveal melanoma with no extrascleral extension was significant (P = 0.001) They were decreased in nonepithelioid cell melanomas. Our results are concordant with other studies on uveal melanoma using locus-specific antibody for HLA antigens (4, 5, 6) .

Immunoreactivity of HLA Class II Antigens in Uveal Melanomas.
HLA class II antigen was decreased in 32 tumors (negative in 27 tumors and heterogeneous in 5 tumors with 30–40% cells stained dull), in-group A with no extrascleral extension (Table 1)Citation . Among the 9 tumors in group B with extrascleral extension, HLA class II antigen was positive (bright staining in 80% of cells) in 4 tumors with liver metastasis and decreased in 5 tumors (heterogeneous in 1 tumor with 40% cells stained dull and negative in 4 tumors) with no liver metastasis. The decreased expression of HLA class II antigen in the uveal melanoma with no extrascleral extension was significant (P = 0.001). HLA class II antigen was decreased in nonepithelioid cell melanomas. Our results are concordant with another study on HLA class II antigens in uveal melanoma (5) .

Immunoreactivity of Proteasomal Subunits in Uveal Melanomas.
LMP2 and LMP10 were decreased in 32 tumors (negative in 25 tumors and heterogeneous with 30% cells with dull staining in 7 tumors) in group A tumors with no extrascleral extension. LMP2 was positive (bright staining with 80% cells staining) in 3 tumors with liver metastasis and decreased in 5 tumors (heterogeneous with 30% cells staining dull in 4 tumors and negative in 1 tumor). LMP10 was positive in 4 tumors with liver metastasis and decreased (heterogeneous with 30% cells staining dull and negative in 2 tumors) in the remaining 5 tumors. {Delta} was decreased in 32 tumors (negative in 25 and heterogeneous in 7 tumors with 30% cells stained dull) in group A with no extrascleral extension. {Delta} was positive in 1 tumor with liver metastasis and negative in 8 tumors in group B. The decreased expression of LMP2 and LMP10 in the uveal melanoma with no extrascleral extension was significant (P = 0.001), and decreased expression was seen in the nonepithelioid cell melanomas.

Immunoreactivity of TAP1 Subunit in Uveal Melanomas.
TAP 1 was decreased in 32 tumors (negative in 24 tumors and heterogeneous with 30% cells stained dull in 8 tumors) with no extrascleral extension. TAP1 was positive (bright staining with 90% cells staining) in all 4 tumors with liver metastasis and decreased in 5 tumors (heterogeneous with 40% cells stained dull and negative in 1 tumor) with no liver metastasis. The decreased expression of TAP1 in the uveal melanoma with no extrascleral extension was significant (P = 0.001). Decreased TAP1 was seen in nonepithelioid cell melanomas.

Immunoreactivity of Chaperone Molecules Tapasin and Calnexin in Uveal Melanomas.
Tapasin and calnexin were decreased in group A tumors with no extrascleral extension (negative in 23 tumors and heterogeneous with 30% cells stained dull in 9 tumors). Tapasin and calnexin were positive in 4 tumors (bright staining with >70% cells stained) with liver metastasis and decreased in 5 tumors (heterogeneous with 30% cells dull stained in 3 and negative in 2 tumors) with no liver metastasis in group B tumors. The decreased expression of Tapasin and calnexin in the uveal melanoma with no extrascleral extension was significant (P = 0.001). Decreased expression of chaperone molecules was seen in nonepithelioid cell melanomas.

Correlation of Immunoreactivity of HLA Class I Antigen and LMP2, LMP10, TAP1, Tapasin, and Calnexin in Uveal Melanomas.
Their expression was concordant in most of the tumors in groups A and B. HLA class I antigens and LMP2, LMP10, TAP1, Tapasin, and calnexin were all decreased in group A tumors with no extrascleral extension and positive in group B tumors with liver metastasis.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study show that HLA class I antigen, ß2-m, and HLA class II antigens and APMs immunoexpression are decreased in primary uveal melanoma lesions with no extrascleral extension (P = 0.001) and are positive in uveal melanomas with liver metastasis. Nonepithelioid cell melanomas have a decreased immunoexpression of the HLA antigens and APM. However, there was no correlation with the LTD. Our results are similar to the previous studies (5 , 6) on uveal melanoma where decreased HLA class I, ß2-m, and HLA class II antigens were associated with favorable outcome, and there was no correlation with nuclear grade, mitosis, MiB-1, tumor-infiltrating lymphocytes, and LTD. Our study also shows that there is a correlation between LMP2 and LMP10 immunoreactivity. There is a reciprocal relationship between LMP2 and {Delta} in mixed and epithelioid melanomas. Immunoexpression of {Delta} subunit of LMP2 was variable in tumors with extrascleral extension.

This study shows for the first time that APMs are decreased in primary uveal melanomas with no extrascleral extension. HLA class I antigen, ß2-m, and the APM expressions were concordant in most of the tumors. This suggests the importance of APM for the expression of HLA class I molecules. Similar decreased expression of HLA class I antigen with decreased expression of the components of the APM has been reported in cervical cancer (16) , cutaneous melanomas (17) in a number of other human tumors (18) , and in tumor cell lines of distinct histology, such as breast cancer (19) , lung cancer (20) , and colon cancer (21) . An important role for proteasomes, TAP, as well as chaperones has been postulated using model cell lines, transfected by the respective genes. Tapasin defective cells show reduced MHC class I surface expression, which could be corrected by tapasin gene transfer (22) . TAP1 knockout mice are defective in stable assembly of MHC class I molecules and show extremely reduced cell surface MHC class I expression (23) . Thus, APMs are necessary for efficient peptide delivery for expression of MHC class I antigen expression. However, recently, proteasome-independent, TAP-independent pathways supporting class I MHC-mediated presentation of exogenous antigens, as well as of endogenously synthesizes viral antigens has been described (24) .

Our findings on HLA class I antigen (with mAb HC10) and TAP1 expression in uveal melanoma are in contrast to studies on cutaneous melanoma (25, 26, 27) . Down-regulation of HLA class I antigen in primary cutaneous melanoma is associated with increased thickness of the lesion, tumor progression, and reduced survival, indicating that HLA class I antigen is an important factor in the behavior of this tumor, which first spreads locally, then lymphatically (25, 26, 27, 28) . In cutaneous melanomas, down-regulation of the expression of HLA class I antigens is associated with a lack of expression of TAP1 and TAP2 correlating with HLA class I down-regulation (with mAb HC10) and reduced survival (17 , 29) . On the other hand, increased expression of HLA class II antigens was correlated with progression in grade of malignancy in cutaneous melanoma (28 , 30) .

This reflects the major role played by HLA class I antigen-restricted, tumor antigen-specific CTL in the control tumor growth in cutaneous melanoma. From this, it follows that HLA class I antigen down-regulation may provide tumor cells with an escape from CTL recognition and destruction. In uveal melanoma, the association of low HLA class I antigen expression in primary uveal melanoma lesions with favorable clinical course may reflect the susceptibility to NK cell-mediated lysis of low HLA class I-expressing melanoma cells invading blood vessels.

The molecular basis of the lack of HLA class I antigen expression on uveal melanoma has not yet been elucidated. Although in cutaneous melanoma, ß2-m gene mutations have been found to be responsible for the lack of HLA class I antigen expression (31) , ß2-m mutations have not been described in uveal melanoma, although a significantly decreased expression of ß2-m was seen in our study and in an earlier study (5) . Thus, the difference in expression of HLA class I antigen and APM in relation to prognosis in uveal melanoma when compared with cutaneous melanomas could be attributable to the immune privileged location in the eye where uveal melanomas occur and the role of NK cells in immune surveillance (32) .

In this regard, the concordant down-regulation of HLA class I antigen and APM in a high percentage of uveal melanomas in our study suggests defects in the regulatory mechanisms that control their expression and not structural defects in the corresponding genes. It is unlikely that mutations are present in multiple genes encoding HLA class I antigen and APM (4) . IFN treatment resulted in significant up-regulation of TAP1/TAP2 proteins, immunoproteasomal subunits, and the MHC class I heavy chain, indicating that ocular melanomas have functional HLA class I presentation machinery capable of responding to IFN type 2 and that transcriptional defects are responsible for the expression of HLA antigens and APM in uveal melanoma (4) . Similar transcriptional defects in the HLA class I antigens and APM have been described in cervical carcinomas (16) .

Several mechanisms may contribute to the association between disease prognosis and HLA class II expression in uveal melanoma. HLA class II antigen-bearing melanoma cells induce the secretion of immunosuppressive cytokine interleukin-10 by T cells, resulting in T-cell anergy (33) that may explain the association between high HLA class II antigen expression in primary uveal melanoma lesions and poor prognosis. Alternatively, the observed correlation may reflect the resistance to NK cell lysis of hematogenously spreading melanoma cells with high HLA class I as well as HLA class II antigen expression, because HLA class I and II antigens may share a common regulatory pathway (34) . This may explain why the expression of HLA class I and II antigens was found to be correlated in our study and in an earlier study (5) .

In conclusion, our study supports the previous studies on HLA class I, ß2-m, and HLA class II antigens in uveal melanoma (5 , 6) and highlights the significance of APM in MHC class I expression in uveal melanoma. Even tumors expressing decreased amounts of HLA class I antigen may be highly susceptible to NK cell-mediated lysis (35) . The underlying molecular mechanisms of expression of APM in uveal melanomas have not been analyzed. Additional studies are needed to understand the precise biological role of APM in uveal melanoma. This will add to our understanding in the development of immunotherapy in uveal melanoma.


   ACKNOWLEDGMENTS
 
We thank Sukumar for assistance in statistical analysis and Dr. R Rajagopal for the linguistic revision.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a grant from the Vision Research Foundation, Sankara Nethralaya, Chennai, India. Back

2 To whom requests for reprints should be addressed, at Medical and Vision Research Foundations, Sankara Nethralaya, 18 College Road, Chennai–600 006, Tamil Nadu, India. Phone: 91-044-28271616; Fax: 91-044-28254180; E-mail: drjb{at}sankaranethralaya.org Back

3 The abbreviations used are: APM, antigen-processing molecule; HLA, human leukocyte antigen; ß2-m, ß 2-microglobulin; LMP, low molecular mass polypeptide; TAP, transporter associated protein; ER, endoplasmic reticulum; mAb, monoclonal antibody; LTD, largest tumor diameter; NK, natural killer cell. Back

4 Internet address: http://www.ihwg.org. Back

Received 9/19/02; revised 5/12/03; accepted 5/15/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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