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 Blood, 15 March 2007, Vol. 109, No. 6, pp. 2496-2504.
Prepublished online as a Blood First Edition Paper on December 5, 2006; DOI 10.1182/blood-2006-07-034231.

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IMMUNOBIOLOGY

In the absence of IGF-1 signaling, IFN-{gamma} suppresses human malignant T-cell growth

Laura Conti1,2, Gabriella Regis1,2, Angela Longo1, Paola Bernabei1, Roberto Chiarle1, Mirella Giovarelli1,2, and Francesco Novelli1,2

1 Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital, Turin, Italy; 2 Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Italy

Several approaches to target insulin-like growth factor-1 (IGF-1) signaling have resulted in the inhibition of the growth of a broad range of tumor cells. Malignant T cells are insensitive to the antiproliferative effects of the interferon-{gamma} (IFN-{gamma})/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1–dependent internalization of the IFN-{gamma}R2 signaling chain. Here we show that human malignant T cells are also resistant to the growth inhibitory effect of both the IGF-1 receptor–specific inhibitor picropodophyllin (PPP) and retrovirus-mediated gene transfer of a dominant negative IGF-1 receptor. However, blockade of IGF-1 receptor perturbs IFN-{gamma}R2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-{gamma}–induced STAT1 activation, a high expression of proapoptotic molecules, and the suppression of malignant T-cell growth both in vitro and in vivo in a severe combined immunodeficiency (SCID) mouse model. These data indicate that the inhibition of IGF-1 signaling combined with IFN-{gamma} administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.


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