Background/aims-Posterior uveal melanoma is the most common intraocular tumour in adults, responsible for the death of approximately 35% of patients. Hepatic metastases are most frequent, and once diagnosed survival is usually less than 1 year. The 1 family of integrins, v 3 and MMP-2 and MMP-9 have been implicated in the metastasis of several types of tumour. To study their involvement in uveal melanoma we analysed the expression of the 1 integrins, v 3, MMP-2, and MMP-9 in 10 primary posterior uveal melanomas, and correlated expression with invasive potential in vitro. Comparable studies were undertaken on cultures of melanocytes. Methods-Expression of integrins was studied by immunohistochemistry, secretion of MMP-2 and MMP-9 by zymography, and the invasive potential was assessed using a transwell model. Results-MMP-2 was secreted by all uveal melanomas and seven of 10 secreted MMP-9. Among uveal melanoma, invasion levels of 4-25% were observed and the major integrins expressed were 1 1, 2 1, 3 1, 5 1, and av 3. Melanocytes did not express 1 1, 4 1, and 6 1. Conclusion-The laminin binding 6 1 integrin was not expressed by either melanocytes or tumours with spindle morphology, which are considered to have a better prognosis. It is possible that expression of the 6 1 integrin may prove useful as a prognostic indicator. (Br J Ophthalmol 2001;85:732-738) Posterior uveal melanoma is the most common primary intraocular tumour in adults.1 Despite new methods of treating the primary melanoma, the survival rate has remained unchanged because of the problem of detection and treatment of metastases.2 Unlike cutaneous melanoma, which metastasises via lymphatic or haematogenous routes to various sites, uveal melanoma mainly disseminates haematogenously and preferentially establishes secondary disease in the liver.3 At least 30% of patients will develop metastases within 10 years of successful treatment of the primary tumour, 4 but at initial presentation, only 1-2% of patients show evidence of hepatic involvement.5 Detection of liver micrometastases is diYcult with currently available clinical tests and it is thought that many patients have subclinical metastases at diagnosis.5 Once metastatic disease has been detected, survival is usually less than 1 year.2 6 Traditional prognostic indicators are based on assessment of the diameter and histological appearance of the tumour 7 8 but it remains diYcult to determine which patients at initial presentation are at high risk of developing metastases.Metastasis is a "multistep" process and tumour cells are required to invade through extracellular matrices (ECMs) at various times during the process. It is proposed that a number of cells detach from the primary tumour and attach via adhesion molecules to components of the ECM or vascular endothelium to be invaded.9 ECM proteins are then degraded by proteolytic enzymes released from the primary tumour or the surrounding stroma.
Summary For the presentation of peptide antigens to cytotoxic CD8+ T lymphocytes of the immune system, the expression of human leukocyte antigen (HLA) class I molecules on the cell surface is necessary. There is increasing evidence that surface HLA class antigen expression is altered in a variety of human tumours by either loss or down-regulation of these molecules, which may be a strategy for evasion of immunosurveillance by malignant cells. This study has examined the expression of HLA class molecules in head and neck squamous cell carcinoma (HNSCC) specimens by immunohistochemistry, using a wide panel of antibodies directed against allele-specific as well as monomorphic determinants of these molecules. The expression of TAP proteins, HLA-DR and the co-stimulatory molecule ICAM-1 were also studied. In addition, the expression of the tumour-associated antigens (TAA) p53 and MAGE genes was determined. Aberrant allelic expression of HLA class antigens was detected in 17 out of 34 (50%) of the specimens stained, whereas HLA class I expression determined by W6/32 staining was found to be heterogeneous in only 2 out of 34 (6%) cases. Decreased expression of ICAM-1 was observed in 12 out of 34 (35%) tumour specimens and de novo expression of HLA-DR (HLA class 11) by carcinoma cells in 13 out of 34 (38%) cases. Aberrant expression of HLA class I antigens was frequently observed in cases in which MAGE genes and p53 overexpression were detected. The altered expression of these immunomodulatory molecules in HNSCC may affect prognosis and has important implications for peptide-based immunotherapy strategies for these patients.
It has previously been reported that MACE-/, -2, -3 and -4 genes are expressed in human cancers including cutaneous melanoma. MAGE-/ and MACE-3 represent targets for specific immunotherapy because they encode peptide antigens which are recognised by cytotoxic T lymphocytes (CTL) when presented by HLA class I molecules, and pilot clinical trials with these peptides are currently in progress. It The MAGE gene family consists of 12 closely related human genes, of which 6, MAGE-I, -2, -3, -4, -6 and -12, are expressed in tumours of different histological types; with the exception of testis and placenta, they are not expressed in normal tissues . Short peptides derived from the processing of MAGE-1 and MAGE-3 gene products are recognised by cytotoxic T lymphocytes (CTL) in the context of HLA class I molecules and therefore represent potential targets for specific immunotherapy of tumours (van der Bruggen et al., 1991Bruggen et al., , 1994a Traversari et al., 1992; Gaugler et al., 1994; Celis et al., 1994).The frequency of expression of MAGE-1, -2, -3 and -4 in cutaneous melanoma is 35, 58,60 and 18%, respectively, with higher proportions of MAGE-positive tumours among metastatic lesions (48, 70, 76 and 22%, respectively) than among primary lesions (16,41,36 and 11%, respectively), suggesting a correlation between tumour progression and incidence of MAGE gene expression . Members of the MAGE gene family are also expressed in breast carcinoma (Brasseur et al., 1992; Russo et al., 1995), non-small cell lung carcinoma (Weynants et ab, 1994; Shichijo et a f , 1995), bladder carcinoma (Patard et al., 1995) and gastric carcinoma (Inoue et al., 1995).The expression of MAGE genes in uveal melanoma tissue has not previously been reported. Uveal melanomas occur with an overall incidence of 5-7/million/year (Shields, 1983); they constitute over 80% of all eye malignancies and are the most common fatal intraocular disease in adults (Egan et al., 1988). Our study has determined the frequency of expression of MAGE-I, -2, -3 and -4 genes in both primary and metastatic uveal melanoma tissue.Peptides processed from the melanocyte lineage-specific proteins tyrosinase, gp100/Pme117 and Melan-A/MART-1, which are present in cutaneous melanoma, have been shown to induce CTLs (Brichard et al., 1993;Bakker et al., 1994;Coulie et al., 1994;Kawakami et al., 1994). Since these antigens may represent additional candidates for peptide immunotherapy of melanoma, the expression of the genes encoding these antigens in uveal melanoma was also assessed in our study. MATERIAL AND METHODS Sample collectionPrimary uveal melanoma tissue was frozen in the vapour phase of liquid nitrogen immediately following enucleation. Metastatic tumour biopsies were frozen in liquid nitrogen immediately after removal (in Sheffield and Brussels) or immediately following pathological dissection (in Lausanne). All samples were subsequently stored at -80°C until use. Samples were collected in the UK (n = 28), Switzerland (n = 16), Belgium (n = 5 ) and France (n = 4). R...
We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.
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