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Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients with Stage III and IV Melanoma

Authors' Affiliations: Departments of ¹ Pathology, ² Medical Oncology, ³ Clinical Chemistry, and ⁴ Clinical Epidemiology and Biostatistics, VU Medical Center, Amsterdam, the Netherlands; ⁵ Lausanne Branch, Ludwig Institute for Cancer Research, University of Lausanne, Switzerland; and ⁶ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

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{at}lab.azu.nl.

Purpose: There have been reports of successful treatment of metastatic melanoma patients with 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 to ASI, paraffin-embedded tissues from stage III or IV melanoma 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-1 expression 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-1 down-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.

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