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Immunology |
1 Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, St. Louis, Missouri and 2 Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York
Requests for reprints: Robert D. Schreiber, Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, Box 8118, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-8747; Fax: 314-747-4888; E-mail: schreiber{at}immunology.wustl.edu.
We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-
. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN- receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN- or IFN-
because of an impairment in the proximal signaling events downstream of both IFN- and IFN-/ß receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN- and IFN-/ß receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and histone deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.
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