Abstract LB-206: Indicators of responsiveness to immune checkpoint inhibitors

Abstract

Abstract Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors, in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to immune checkpoint inhibitor therapy, which revealed specific biological signatures that can stratify metastatic melanoma patients as responders or non-responders. Furthermore, our findings provide the first evidence of epigenetically-driven epithelial-mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Furthermore, we show E-cadherin is transcriptionally regulated by the EZH2-catalyzed H3K27me3 epigenetic mark in non-responding tumors. The repressive epigenetic mark H3K27me3, has known roles in melanoma pathogenesis and progression, but not in response to immunotherapies. Here, we provide the first report of an epigenetic program directly linking elevated levels of H3K27me3 to non-responding tumors. Our results have broad implications for immune checkpoint inhibitor therapy in a variety of carcinomas as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and specific pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness. Citation Format: Bradley D. Shields, Fade Mahmoud, Erin M. Taylor, Stephanie D. Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel Mackintosh, Ricky Edmondson, Sara C. Shalin, Alan J. Tackett. Indicators of responsiveness to immune checkpoint inhibitors [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 LB-206. doi:10.1158/1538-7445.AM2017-LB-206