Cellular immune response in human melanoma : Insights for patient tailored therapy

Purpose: There have been reports of successful treatment of metastaticmelanomapatientswith active specific immunotherapy (ASI) using irradiated autologous tumor cell vaccination. It is still unknown why some patients respond and others do not. Tumor cells can evade the immune system, for example through interference with antigen presentation by down-regulation of MHC molecules or expressing proteins interfering with cytotoxic lymphocyte ^ induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9). Experimental Design: PI-9 expression was detected in melanoma cell lines. To investigated if PI-9 is important in the response toASI, paraffin-embedded tissues from stage III or IVmelanoma patients were stained. Results: PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival. Moreover, loss of MHC-1expression frequently occurs during tumor progression but is not associated with poor clinical outcome. Interestingly, melanoma patients with a favorable clinical outcome after ASI therapy usually have high percentages of activated (granzyme B ^ positive) tumor-infiltrating lymphocytes at time of first diagnosis and low percentages of activated lymphocytes at time of recurrent tumor. Conclusions: Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy. Melanoma is a highly malignant, increasingly common tumor for which treatment failure is a well-known problem. Although melanoma accounts for only 4% of all skin cancers, it causes the greatest number of skin cancer–related deaths worldwide. There has been a worldwide increase in incidence of melanoma over the last four decades with the highest incidence in Australia and New Zealand (1). Early detection and complete surgical excision of melanoma is the best manner to reduce mortality. In case of a regional lymph node metastasis (stage III), 5-year survival is dependent on the number of involved lymph nodes (2). Despite a large number of clinical trials to test anticancer strategies, the median survival time of advanced melanoma patients (stage IV) is still no longer than 6 to 10 months (3). Novel immune therapeutic strategies aiming at the induction, enhancement, and prolongation of the immune response against malignant melanoma cells are currently being developed and applied in clinical practice (4). The aim of these therapies is to induce a tumor-specific immune response, which will eliminate the tumor cell often by means of apoptosis induction. Although some therapies seem promising, the results obtained are variable and it is still unknown why some patients respond and others do not. We have previously shown that active specific immunotherapy (ASI) is probably beneficial in a fraction of stage III and stage IV melanoma patients when given in the adjuvant setting (5). In these patients, the delayed-type hypersensitivity (DTH) response against the tumor cell vaccine strongly correlated with survival, suggesting that the immune response is involved in outcome following ASI therapy. Cancer Therapy: Preclinical Authors’Affiliations: Departments of Pathology, Medical Oncology, Clinical Chemistry, and Clinical Epidemiology and Biostatistics, VU Medical Center, Amsterdam, the Netherlands; Lausanne Branch, Ludwig Institute for Cancer Research, University of Lausanne, Switzerland; and Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands Received 2/10/05; revised 5/24/05; accepted 6/3/05. Grant support:VUMedical Center. 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 with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Jean A. Kummer, Department of Pathology (H04.312), University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. Phone: 31-30-2506565; Fax: 31-30-2544990; E-mail: j.a. kummer@ lab.azu. nl. F2005 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-0306 www.aacrjournals. org Clin Cancer Res 2005;11(17) September 1, 2005 6400 63 Expression of the Granzyme B inhibitor PI-9 in melanoma