This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, W. Articles by Kirkwood, J. M. Search for Related Content PubMed PubMed Citation Articles by Wang, W. Articles by Kirkwood, J. M.

Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFN2b

Authors' Affiliations: ¹ Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute; ² Department of Surgery, Magee Women's Hospital; ³ Department of Pathology, University of Pittsburgh Medical Center-Shadyside; ⁴ Department of Dermatology, University of Pittsburgh Medical Center; ⁵ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; and ⁶ Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: John M. Kirkwood, Melanoma and Skin Cancer Program, Department of Medicine, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Avenue, Pittsburgh, PA 15213-2584. Phone: 412-623-7707; Fax: 412-623-7704; E-mail: KirkwoodJM{at}upmc.edu.

Purpose: The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFN2b (HDI) in relation to the balance of pSTAT1 and pSTAT3.

Experimental Design: We evaluated STAT1 and STAT3 jointly as mediators of IFN effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies.

Results: HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).

Conclusion: IFN2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.

This article has been cited by other articles:

				M. Fujita, X. Zhu, K. Sasaki, R. Ueda, K. L. Low, I. F. Pollack, and H. Okada Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma J. Immunol., February 15, 2008; 180(4): 2089 - 2098. [Abstract] [Full Text] [PDF]

				G. B. Lesinski, J. Trefry, M. Brasdovich, S. V. Kondadasula, K. Sackey, J. M. Zimmerer, A. R. Chaudhury, L. Yu, X. Zhang, T. R. Crespin, et al. Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-{alpha} Compared with Immune Effector Cells Clin. Cancer Res., September 1, 2007; 13(17): 5010 - 5019. [Abstract] [Full Text] [PDF]