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Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN- Compared with Immune Effector Cells

Authors' Affiliations: ¹ Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, ² Department of Surgery, ³ Integrated Biomedical Sciences Graduate Program, ⁴ Department of Pathology, and ⁵ The Center for Biostatistics, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, and ⁶ Primetrics, Inc., Hilliard, Ohio

Requests for reprints: William E. Carson III, Department of Surgery, The Ohio State University, N924 Doan Hall 410, West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-293-3465; E-mail: William.Carson{at}osumc.edu.

Purpose: IFN- is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-.

Experimental Design: Tyr⁷⁰¹-phosphorylated STAT1 (P-STAT1) was measured by flow cytometry in IFN-–stimulated human melanoma cell lines, melanoma cells derived from patient tumors, and peripheral blood mononuclear cells (PBMC). Expression of other Janus-activated kinase (Jak)-STAT intermediates (STAT1, STAT2, Jak1, tyrosine kinase 2, IFN- receptor, STAT3, and STAT5) was evaluated by flow cytometry, immunoblot, or immunohistochemistry.

Results: Significant variability in P-STAT1 was observed in human melanoma cell lines following IFN- treatment (P < 0.05) and IFN-–induced P-STAT1 correlated with the antiproliferative effects of IFN- (P = 0.042). Reduced formation of P-STAT1 was not explained by loss of Jak-STAT proteins or enhanced STAT5 signaling as reported previously. Basal levels of P-STAT3 were inversely correlated with IFN-–induced P-STAT1 in cell lines (P = 0.013). IFN-–induced formation of P-STAT1 was also variable in melanoma cells derived from patient tumors; however, no relationship between P-STAT3 and IFN-–induced P-STAT1 was evident. Because IFN- acts on both tumor and immune cells, we examined the ability of IFN- to induce P-STAT1 in patient-derived melanoma cells and PBMCs. IFN- induced significantly lower levels of P-STAT1 in melanoma cells compared with matched PBMCs (P = 0.046). Melanoma cells and human melanocytes required 10-fold higher IFN- doses to exert P-STAT1 levels comparable with PBMCs.

Conclusions: Melanoma cells are variable in their IFN- responsiveness, and cells of the melanocytic lineage exhibit a lower capacity for IFN-–induced Jak-STAT signaling compared with immune cells.

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