Abstract LB-292: Role of TLR engagement in TIL-B and clinical implications for ovarian cancer

Abstract

Abstract Ovarian cancer is the eighth most common cancer in women and represents the most lethal gynecological cancer, where less than a third of the women survive longer than five years after diagnosis. The identification of novel therapeutic strategies is urgently needed to improve patient prognosis. Solid and hematologic malignant cells express a broad range of Toll-like receptors (TLR). Activation of TLR signaling through recognition of pathogen-associated molecular patterns leads to the transcriptional activation of genes encoding for pro-inflammatory cytokines, chemokines and co-stimulatory molecules. Solid tumor development has been associated with TLR engagement through both growth acceleration and immune escape, and epidemiological studies reported a link between TLR expression by ovarian tumor cells and chemoresistance. We previously observed a large proportion of B cells in the immune infiltrate of mouse ovarian tumors and in human ascites from ovarian cancer patients, but the role of TLR stimulation in ovarian tumor-infiltrating lymphocyte B (TIL-B) remains unclear. The objective of this study is to investigate the functional consequences of TLR expression and engagement on TIL-B in ovarian cancer. Our work has been carried in a transgenic mouse model (TgMISIIR-Tag) that spontaneously develops tumors through the expression of SV40 T antigen under the Mullerian Inhibitor Receptor type II (MISIIR) promoter. TgMISIIR-Tag tumors resemble human serous ovarian cancer, the most common type of ovarian cancer. Microarrays and flow cytometry analyzes were used to characterize the phenotype of TIL-B after CD19 magnetic sorting ex vivo or after in vitro culture. We first found that TIL-B significantly over-expressed transcripts encoding for inflammatory cytokines, growth factors, adhesion molecules and chemokines, compared to B cells from spleens and lymph nodes of healthy or tumor bearing mice. We also showed that B cells from TgMISIIR-TAg tumors and from ascites of ovarian cancer patients over-expressed TLR2, TLR4 and/or TLR9, to compare with mouse splenic or human peripheral B cells, respectively. In addition, five days co-culture of TIL-B with ovarian tumor cells and TLR4 and TLR 9 agonists further increased TLR4 and TLR9 expression, as well as the expression of CD5 and CD1d costimulatory molecules and IL10 production. Concomitant treatment with TLR antagonists reduced TLR expression and IL-10 production of TIL-B. In vivo studies aiming to interrogate the role of TLR engagement on TIL-B in ovarian cancer are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2011-LB-292