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Major Histocompatibility Antigens and Antigen-Processing Molecules in Uveal Melanoma1

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Vol. 9, 4159–4164, September 15, 2003 Clinical Cancer Research 4159 Major Histocompatibility Antigens and Antigen-processing Molecules in Uveal Melanoma1 Subramanian Krishnakumar, Dhiraj Abhyankar, tigens and the APM was seen in nonepithelioid cell melano- Amirtha Lakshmi Sundaram, mas. There was no correlation with largest tumor diameter. Conclusions: Our data suggest decreased expression of Vaijayanthi Pushparaj, HLA, and APM are seen in uveal melanomas with no ex- Mahesh Palanivelu Shanmugam, and trascleral extension and in nonepithelioid cell melanomas. 2 Jyotirmay Biswas Decreased expression of APM may contribute to decreased Department of Ocular Pathology [S. K., A. L. S., V. P., J. B.] and HLA class I antigen expression. 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, INTRODUCTION New York 142631 [D. A.] 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 ABSTRACT metastatic disease, usually in the liver, is between 2 and 7 Purpose: Malignant transformation of cells is fre- months. No effective treatment for metastatic disease is yet quently associated with abnormalities in the human leuko- available (1). The therapy of uveal melanoma remains problem- cyte antigen (HLA) expression. These abnormalities may atic because of the high rate of metastatic dissemination, irre- play a role in the clinical course of the disease, because HLA spective of the success of treatment of the primary tumor. When antigens mediate interactions of tumor cells with T cells and metastatic disease is diagnosed, patient survival is usually Ͻ1 natural killer cells. Uveal melanoma is a highly malignant year (2). Immunotherapy has generated a lot of interest in the tumor of the eye and is characterized by hematogenic spread treatment of metastatic uveal melanomas. MHC and the APM3 to liver. Antigen-processing molecules (APMs) are necessary have generated interest in immunotherapy in many tumors (3). for efficient expression of HLA class I antigens. We studied In uveal melanomas, abnormalities in the HLA class I ␤ the expression of HLA antigens and the APM in uveal antigen, 2-m, and HLA class II antigens have been reported melanomas by immunohistochemistry and correlated clini- (4–6). The pathway of APM involved in the generation of HLA copathologically. class I molecule has been well defined recently. These include ␤ Experimental Design: HLA class I antigen, 2-micro- the low molecular proteasomal complexes, generating antigenic ␤ globulin ( 2-m), HLA class II antigens, and the APM com- peptide fragments comprising of LMP 2, ␤ subunit of LMP2, prising proteasomal subunits low molecular mass polypep- i.e., ⌬, LMP 7, and the recently described multicatalytic en- tide (LMP) 2, ␤-subunit of LMP2-⌬, LMP 10, transporter dopeptidase complex-like-1, also referred to as LMP10. LMP10 associated protein 1 subunit, and chaperone molecules tapa- is not encoded in the MHC locus in contrast to LMP2 and sin and calnexin were studied in 41 primary uveal melanoma LMP7. LMP10 is necessary for the expression of LMP 2. The archival specimens by immunohistochemistry. Immuno- new proteasomal ⌬is highly homologous to LMP2 and ex- analysis was done by a semiquantitative method and corre- pressed in a reciprocal manner with LMP2. lated with extrascleral extension, cell types, and the largest The transporter proteins TAP1, TAP2 translocate peptides tumor diameter. from the cytosol to the ER. Different ER-resident chaperones ␤ Results: HLA class I antigen, 2-m, HLA class II anti- calnexin, calreticulin, the binding protein tapasin, stabilize gen, and the APM were decreased (negative staining in 29 MHC class I molecules during their folding and/or assembly in tumors and dull staining in 3 tumors) in 100% (32 of 32) the ER or assist their loading with peptides. Binding of high -affinity peptides to MHC class I molecules leads to the disso (0.01 ؍ uveal melanomas with no extrascleral extension. (P and positive (bright staining) in 67% (4 of 9) tumors with ciation of this TAP complex and the exit of the ternary MHC ␤ liver metastasis. Decreased immunoexpression of HLA an- class I/ 2-m/peptide complex from the ER through the golgi for presentation to CD8ϩ CTLs. Deficiency of LMP, TAP, and the chaperone proteins reduces the supply and repertoire of peptides available for binding to MHC-1 (7–9). Received 9/19/02; revised 5/12/03; accepted 5/15/03. In contrast to a number of studies (4–6) demonstrating The costs of publication of this article were defrayed in part by the HLA class I antigen down-regulation in primary uveal mela- 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. 3 The abbreviations used are: APM, antigen-processing molecule; HLA, 2 ␤ ␤ To whom requests for reprints should be addressed, at Medical and human leukocyte antigen; 2-m, 2-microglobulin; LMP, low molec- Vision Research Foundations, Sankara Nethralaya, 18 College Road, ular mass polypeptide; TAP, transporter associated protein; ER, endo- Chennai–600 006, Tamil Nadu, India. Phone: 91-044-28271616; Fax: plasmic reticulum; mAb, monoclonal antibody; LTD, largest tumor 91-044-28254180; E-mail: [email protected]. diameter; NK, natural killer cell. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2003 American Association for Cancer Research. 4160 Role of HLA and Antigen-processing Molecules Table 1 HLA antigen and APMs immunoreactivity in Group A uveal melanomas with no extrascleral extensiona Transporter Chaperone MHC class antigens Proteasomal subunits protein molecules LTD Cell HLA HLA Follow-up ␤ ⌬ No. in mm type class I 2-m class II LMP 2 LMP 10 TAP 1 Tapasin Calnexin in months 1 11 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 60 mA 2 11 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 60 mA 3 14 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 46 mAI 4 11 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 56 mA 5 10 S Neg Neg Neg Neg Neg Neg Neg Het Neg 36 mA 6 15.5 S Neg Neg Neg Neg Neg Neg Het Neg Het 31 mA 7 16 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 30 mA 8 8 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 28 mA 9 9.5 S Neg Neg Neg Neg Het Neg Neg Het Neg 24 mA 10 9 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 30 mA 11 7.5 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 24 mA 12 10 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 31 mA 13 7 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 26 mA 14 15.5 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 32 mA 15 16 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 30 mA 16 12.5 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 6 mA 17 9 S Neg Neg Neg Neg Neg Neg Neg Neg Neg 20 mA 18 17 M Neg Neg Neg Neg Neg Neg Neg Neg Neg 18 mA 19 11 M Neg Neg Neg Neg Het Neg Neg Neg Neg 14 mA 20 16.9 M Neg Neg Neg Neg Neg Neg Neg Neg Neg 14 mA 21 9 M Neg Neg Neg Neg Het Neg Neg Neg Neg 18 mA 22 12 M Neg Neg Neg Het Neg Het Het Het Het 13 mA 23 15 M Neg Neg Neg Neg Neg Neg Neg Neg Neg 10 mA 24 23 M Neg Neg Neg Neg Neg Neg Neg Neg Neg 8 mA 25 14 M Neg Neg Neg Neg Het Neg Neg Neg Het 8 mA 26 20 E Het Het Het Het Neg Het Het Het Het 18 mA 27 4 E Het Het Het Het Neg Het Het Het Het 22 mA 28 14 E Neg Neg Neg Neg Neg Neg Neg Neg Neg 16 mA 29 6.5 E Het Het Neg Het Neg Het Het Het Het 24 mA 30 20 E Het Neg Het Het Het Het Het Het Het 14 mA 31 15 E Het Het Het Het Het Het Het Het Het 20 mA 32 12.6 E Het Het Het Het Neg Het Het Het Het 7 mA S, spindle; M, mixed; E, epithelioid; Neg, negative; Het, heterogeneous; Pos, positive; m, months; A, alive; D, dead. noma lesions with favorable outcomes, there is little information and liver metastasis; communications received from the rela- about the expression of APM, which are responsible for gener- tives of the patients, and they all had liver metastasis according ating peptides and efficient expression of HLA class I antigens. to their family physicians). The follow-up data available from Therefore, in this present study, we investigated the immuno- the medical records of all of the patients are given in Tables 1 ␤ reactivity of HLA class I antigen, 2-m, HLA class II antigen, and 2. The minimum follow-up was for 6 months, and the and APM comprising proteasomal subunits LMP2, ␤ subunit of maximum follow-up was for 60 months. LMP2, i.e. ⌬, LMP10, transporter protein TAP1 subunit, and Inclusion and Exclusion Criteria. Inclusion criterion chaperone molecules tapasin and calnexin and correlated with was that all of the patients were treated by enucleation. Exclu- extrascleral invasion, cell types, and LTD in uveal melanomas. sion criteria included patients who had received pre or intraop- erative adjunctive treatments, such as radiotherapy and cryo- MATERIALS AND METHODS therapy.
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