Abstract 2637: Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition

Abstract

Abstract The incidence and mortality rates of hepatocellular carcinoma caused by metabolic dysfunction-associated fatty liver disease (MAFLD) have been increasing in recent decades, emphasizing the urgent need for new therapeutic approaches. Emerging evidence suggests that approximately 80% of super-enhancer RNAs (seRNAs) undergo selective m6A modifications. seRNA and m6A modifications have been implicated in the progression of various cancers, making them potential targets for therapeutic intervention. Based on our previous research, we hypothesize that the lack of m6A modification on the super-enhancer of CCL4 may contribute to the reduced expression of the CCL4 gene in HCC.To validate our hypothesis, we employ nano-chromatin immunoprecipitation combined with high-throughput sequencing (nano-ChIP-seq), m6A-seq (m6A-seq), single-cell RNA sequencing (scRNA-seq) on multiple models including clinical samples, cell lines, and mouse models. Interestingly, we have made a significant discovery that overexpression of CCL4 in tumor cells enhances the infiltration of CD8+ T cells, which are crucial for anti-tumor immune responses. In contrast, normal tissue cells undergo m6A modification on the CCL4 seRNAs, while this modification is notably absent in cancerous tissue. Consequently, the reduced expression of CCL4 could impair the tumor-killing capabilities of CD8+ T cells and facilitate immune evasion by the tumor.Furthermore, our results shed light on the underlying molecular mechanisms involving super-enhancers and m6A modifications in the regulation of immune escape in MAFLD HCC. We identify the specific super-enhancer and downstream regulatory genes influenced by m6A modification in MAFLD-associated HCC, providing valuable insights and novel targets for the treatment of this condition. Citation Format: Liangliang Xu. Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition [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 2637.