Abstract 7547: Enhancers as targets for improvements in immunotherapy

Abstract

Abstract Role of epigenetic elements in mediating tumor immune interaction remains poorly understood. We previously identified enrichment of active enhancer states on a set of genomic loci in non-responders to immune checkpoint blockade (ICB) therapy. We noted that the activated non-responder enhancers marked a group of key regulators of in melanoma cells that are known to mediate resistance to ICB therapy and several checkpoint receptors in T cells. Through spatial epigenomics (Spatial ATAC and CUT&Tag) approaches, we identified the tumor-immune niches harboring unique gene regulatory elements and transcription factors that could mediate melanoma-T cell interaction. Further, we aimed to identify functional epigenetic elements through custom CRISPRi screening of enhancers in patient tumor-derived melanoma and T cells. CRISPRi approaches identified novel functional enhancers that mediate T cell mediated killing. For example, we identified distal c-MET enhancers as important contributors to T cell mediated killing. In T cells, we identified enhancer hubs that target multiple genes. These hubs could be targeted to activate interferon gamma, reduce T cell exhaustion, and improve T cell mediated killing of melanoma cells. Such enhancer hubs could serve as targets in the ex vivo setting to improve adoptive T cell therapy. Overall, our results suggest that enhancers with unique spatial patterns in melanoma tumors contribute to the response to immunotherapy and could be novel targets for therapy. Citation Format: Anand Singh, Veena Kochat, Emre Arslan, Suresh Satpati, Wentao Deng, Sandeep Yadav, Efthalia Bataki, Cassian Yee, Kunal Rai. Enhancers as targets for improvements in immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7547.