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Constitutive Expression and Costimulatory Function of LIGHT/TNFSF14 on Human Melanoma Cells and Melanoma-Derived Microvesicles

¹ Human Tumor Immunobiology Unit, Department of Experimental Oncology, ² Department of Pathology, and ³ Melanoma and Sarcoma Unit, Department of Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

Requests for reprints: Andrea Anichini, Human Tumor Immunobiology Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-22-390-2817; Fax: 39-22-390-2630; E-mail: andrea.anichini{at}istitutotumori.mi.it.

Neoplastic cells are thought to have defective expression of costimulatory molecules. However, in this study, we show that human melanoma cells express LIGHT/TNFSF14, a ligand of herpesvirus entry mediator on T cells and of lymphotoxin ß receptor on stromal cells. In vitro, melanoma cells stained for LIGHT in the intracellular compartment, with weak or negative cell surface expression. However, LIGHT was expressed on tumor-derived microvesicles released from melanoma cells. In vivo, LIGHT was found in metastatic lesions, and the extent of lymphotoxin ß receptor expression on the stromal cells was significantly associated with a "brisk" T-cell infiltrate in the neoplastic tissue. In the lesions with a brisk T-cell infiltrate, stromal cells surrounding the tumor also stained for the T-cell attractant chemokine CCL21. The intratumoral T lymphocytes frequently expressed herpesvirus entry mediator and were characterized by a differentiated phenotype. Coculture of lymphocytes with LIGHT⁺ melanoma-derived microvesicles or even with LIGHT⁺ melanoma cells in the presence of interleukin-2 costimulated LIGHT-dependent CD3⁺CD8⁺ T-cell proliferation. However, lymphocyte coculture with LIGHT⁺ microvesicles in the presence of interleukin-2 was also associated with an apoptotic response as documented by increased binding of Annexin V by CD3⁺CD8⁺ T cells. These data suggest that LIGHT constitutively expressed in human melanoma cells and microvesicles may contribute to regulate T-cell responses to tumor cells.

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