Abstract 3669: Autocrine interleukin/STAT3 signaling in breast implant-associated T cell anaplastic large cell lymphoma cell lines suggests a mechanism for tumor progression and effective therapy

Abstract

Abstract Recently, over 80 cases of anaplastic large-cell kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphomas (T-ALCL) have been identified worldwide in patients with textured saline and silicone breast implants. These breast implant-associated T-ALCL cases are striking for their homogeneous clinical presentation and pathology that is distinct from established classes of ALCL. In order to understand the nature of this newly emerged clinical entity, we have established three new cell lines, designated T cell Breast Lymphoma (TLBR) -1, -2, and -3, from patient primary tumor biopsy specimens. Characterization of these pre-clinical models confirmed fidelity to the original tumor biopsy specimens and highlighted unique features that may aid the development of effective treatments for these cancers. Gene expression analysis demonstrated significant up-regulation of survivin and down-regulation of pro-apoptotic genes (BID, BAK, BBC3) by all TLBR cell lines relative to healthy donor T cells. This preliminary finding prompted examination of upstream regulators of cell survival in T cells, namely the interleukin signaling associated with the JAK/STAT pathway. TLBR cell lines were found to secrete high levels of IL-6 and IL-10, and were strongly positive for the cognate receptors. The TLBR cell lines also showed elevated levels of STAT3 and pSTAT3 by immunoblotting techniques, along with a simultaneous reduction in expression of the pSTAT3 phosphatase, SHP-1. These results implicate an unregulated autocrine STAT3 pathway present in the TLBR cell lines that strongly contributes to their tumorigenesis. Assays of various inhibitors of this pathway support this hypothesis since targeting of STAT3 with the tyrosine kinase inhibitor, Sunitinib, led to dramatic in vitro cell death in all TLBR cell lines. More specific inhibition of STAT3 with S3I-201 had comparable results with Sunitinib. Furthermore, IL-6 neutralization by a monoclonal antibody or SHP-1 restoration by 5-azacytidine treatment also demonstrated moderate efficacy in inhibiting TLBR cell line growth in vitro. These discoveries strongly suggest the use of these reagents in the clinical treatment of Breast Implant Associated T-ALCL. The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived, and as such provide valuable preclinical models to study the unique biology and provide clinicians with improved knowledge for treatment and diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3669. doi:1538-7445.AM2012-3669