Abstract A002: Epigenetic Regulation of the GDF15 Immune Checkpoint Determines Sensitivity of Atypical Teratoid/Rhabdoid Tumors to Natural Killer Cell Immunotherapy

Abstract

Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric central nervous system malignancies characterized by poor clinical outcomes despite intensive multimodal therapy, including surgery, chemotherapy, and radiation. Although molecular classification has improved our understanding of ATRT biology, these advances have not yet translated into effective therapies for patients. Here, we investigated natural killer (NK) cell-based immunotherapy as a novel therapeutic strategy for ATRTs and identified subgroup-specific differences in tumor sensitivity to NK cell-mediated cytotoxicity driven by variable expression of the immunomodulatory cytokine - growth and differentiation factor 15 (GDF15). ATRTs are almost universally defined by loss of SMARCB1, a core component of the ATP-dependent SWI/SNF chromatin-remodeling complex, resulting in widespread dysregulation of lineage-specific enhancers. Through integrated multi-omic analyses of patient tumors and ATRT cell lines, including RNA-seq, ATAC-seq, DNA methylation profiling, ChIP-seq, and chromatin conformation capture (3C) assays, we identified subgroup-specific differences in the epigenetic regulation of the GDF15 locus. Differential DNA methylation at the GDF15 promoter, distinct histone modification patterns at both the promoter and a previously unrecognized upstream enhancer, and long-range promoter-enhancer interactions collectively contributed to subgroup-dependent variability in GDF15 expression. Mechanistically, DNA methylation-dependent chromatin occupancy by two antagonistic regulatory proteins, RE1-silencing transcription factor (REST) and CCCTC-binding factor (CTCF), governed the epigenetic architecture of the GDF15 locus. REST-mediated displacement of CTCF silenced GDF15 expression and overcame tumor-mediated suppression of NK cell function. Genetic disruption of this regulatory axis, as well as blockade of GDF15 with neutralizing antibodies, reversed NK cell suppression in vitro and significantly enhanced NK cell-mediated antitumor activity in orthotopic intracranial ATRT models. Collectively, these findings reveal a novel epigenetic mechanism regulating immune evasion in ATRTs. GDF15 represents a therapeutically actionable immune checkpoint and its combination with NK cell-based immunotherapy could offer a promising treatment strategy for subsets of patients with ATRTs and other GDF15-expressing brain tumors.