Abstract 3998: Alerting the immune system by removing epigenetic silencing of Th1 chemokines

Abstract

Abstract BACKGROUND: Solid tumors employ multiple mechanisms to evade an immune response. However, the potential to enhance the immune response to cancer has been proven in several malignancie and is under investigation in many others, including primary CNS tumors. Brain tumors in particular lack robust T-cell infiltration. Recent studies have found that certain tumors can be induced to express T-cell attracting chemokines, CXCL9 and CXCL10, by interferon gamma (IFNg). This response is further amplified using methyltransferase inhibitors (Peng, et al. Nature 2015. Vol 527: 249-253.), resulting in increased Tcell trafficking to tumors both in vitro and in vivo. We hypothesized that T-cell trafficking to brain tumors could likewise be enhanced with DNA and histone methyltransferase inhibitors to induce CXCL9 and CXCL10 transcription. METHODS: Assays were performed on 7 human glioma brain tumor cell lines. CXCL9 and CXCL10 expression were measured by real-time PCR. Two commercially available methyltransferase inhibitors, 5-AZA-dC and GSK126, were utilized to demethylate DNA and histone H3 (K9 and K27), respectively. Histone methylation status was examined using Western blot. T-cell migration was measured using transwell migration assays. RESULTS: IFNg increased CXCL9 and CXCL10 transcription in brain tumor lines. GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 compared to IFNg alone. Migration assays confirmed T-cell trafficking towards chemokines produced by tumor cells in response to methyltransferase inhibitors. CONCLUSIONS: These studies demonstrate that brain tumors express T-cell attracting chemokines CXCL9 and CXCL10 in response to IFNg. Further, GSK126 and the combination of GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 transcription by real-time PCR and T-cell trafficking by migration assay. Together, these data provide a potential means to increase T-cell trafficking into tumors and potentially enhances the efficacy of immune therapies for brain tumors. Citation Format: Heather M. Sonnemann, Amber J. Giles, Caitlin M. Reid, Marsha-Kay N. Hutchinson, Deric M. Park, Mark R. Gilbert. Alerting the immune system by removing epigenetic silencing of Th1 chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3998. doi:10.1158/1538-7445.AM2017-3998