TMIC-01. ALERTING THE IMMUNE SYSTEM BY REMOVING EPIGENETIC SILENCING OF TH1 CHEMOKINES

Abstract

Solid tumors employ multiple mechanisms to evade immunologic detection and destruction. However, the potential to enhance the immune response to cancer has been proven in several malignancies and is under investigation in many others, including primary CNS tumors. Brain tumors, in particular, lack robust T-cell infiltration, suggesting poor immune surveillance. Recent studies have found that tumor cells express T-cell attracting chemokines, CXCL9/10, in response to interferon gamma (IFNg). Chemokine expression can be further amplified by drugs that prevent epigenetic silencing, such as histone methyltransferase inhibitors or histone deacetylase (HDAC) inhibitors. This approach increases T-cell trafficking to tumors in vivo and enhances the anti-tumor efficacy of checkpoint blockade. We hypothesized that T-cell trafficking to brain tumors could be increased by epigenetically enhancing CXCL9/10 expression. Assays were performed on human glioma brain tumor cell lines. CXCL9/10 expression were measured by real-time PCR and Western blot. GSK126, a commercially available methyltransferase inhibitor, was utilized to demethylate histone H3 (K9/K27). LB201 (Lixte Biotechnology, Setatuket, NY) was used to inhibit class 1/2 HDAC. Histone methylation and acetylation status were examined using Western blot analysis. T-cell migration was measured using transwell migration assays. expression of CXCL9/10 was induced by IFNg in brain tumor lines. Chemokine expression was further increased when cells were treated with GSK126 and LB201 compared to IFNg alone. Migration assays confirmed that tumor cells treated with GSK126 and LB201 released T-cell chemotactic factors that increased T-cell migration. These studies demonstrate that brain tumors express T-cell attracting chemokines CXCL9/10 in response to IFNg. Further, GSK126 and the combination of GSK126 and LB201 enhanced expression of CXCL9/10, resulting in increased T-cell migration toward tumor cells. Together, these data provide a potential means to enhance the efficacy of immune therapies for brain tumors by promoting T-cell trafficking toward tumor cells.