Inhibition of p-STAT3 enhances IFN-α efficacy against metastatic melanoma in a murine model

Ling Yuan Kong, Alexander Gelbard, Jun Wei, Chantal Reina-Ortiz, Yongtao Wang, Eric C. Yang, Yared Hailemichael, Izabela Fokt, Arumugam Jayakumar, Wei Qiao, Gregory N. Fuller, Willem W. Overwijk, Waldemar Priebe, Amy B. Heimberger

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Purpose: Melanoma is a common and deadly tumor that upon metastasis to the central nervous system has a median survival duration of <6 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. We hypothesized that WP1193, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of IFN-α against metastatic melanoma. Experimental Design: Combinational therapy of STAT3 blockade agents with IFN-α was investigated in a metastatic and an established syngeneic intracerebral murine tumor model of melanoma. The immunologic in vivo mechanisms of efficacy were investigated by T-cell and natural killer (NK) cell cytotoxic assays. Results: IFN-α immunotherapy was synergistic with WP1193 showing marked in vivo efficacy against metastatic and established intracerebral melanoma. At autopsy, it was noted that there was a decreased trend in mice with melanoma developing leptomeningeal disease treated with combinational therapy. The combinational approach enhanced both NK-mediated and T-cell-mediated antitumor cytotoxicity. Conclusions: The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-α immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach.

Original languageEnglish (US)
Pages (from-to)2550-2561
Number of pages12
JournalClinical Cancer Research
Volume16
Issue number9
DOIs
StatePublished - May 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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