Tumor Infiltrating Lymphocytes in Uveal Melanoma: A Link with Clinical Behavior?

Abstract

Experimental and clinical evidence indicate that immunological mechanisms might be important in the clinical course of uveal malignant melanoma (UMM). We analyzed the amount and phenotype of tumor infiltrating lymphocytes (TIL) and the expression of the apoptosis-inducing molecule Fas and its ligand, FasL, on tumor cells and TIL in a selected series of UMM with the aim to establish if a correlation between their expression and the clinical behavior of UMM exists. TIL phenotype and Fas/FasL expression were evaluated by immunohistochemistry in 61 cases of formalin-fixed, paraffin-embedded UMM. Results were compared with the follow-up data of patients. Most of the UMM showed a prevalence of CD8+ CD3+ T lymphocytes, or CD4+ and CD8+ cells in equal amounts. UMM showed a variable expression of FasL, ranging from 0 to > 40% of neoplastic cells. Fas was always expressed in TIL, although with a variable extent. A subgroup of UMM showed in TIL a strongly reduced or even absent expression ofTCR~-chain, involved in activation ofT-lymphocytes. This subgroup was characterized by a worse outcome. We hypothesized that an impaired cytotoxic immune response due to the loss of the~ chain expression plays a primary role in the biological course of UMM. Our results indicate that the overcoming of the impairment of TCR function may represent a prerequisite for the development of new therapeutic strategies for managing UMM, suggesting that elimination of tumor cells may be possible by activation of cytotoxic cells present within ocular melanomas.Uveal malignant melanoma (UMM) is the most common malignant primary intra-ocular tumor in adults (1-4). It accounts for 70-88% of all ocular tumors, with an annual incidence of approximately 6 cases per milIion per year (1-4). The therapy of UMM is problematic due to the high rate of metastatic dissemination (5). Treatment therapies for this tumor warrant further studies. To date, enucleation remains as effective as the recent eyesparing approaches (6-7). When metastatic disease is diagnosed, patient survival is generally less than 7 months (8-11). During the "dormant" period from diagnosis of primitive tumor and the occurrence of metastasis, chemo-and immunotherapy have also been considered (12).UMM arises in the immune-privileged ocular

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