IDDF2024-ABS-0199 ELOVL fatty acid elongase 1 facilitates NAFLD-related HCC progression by shaping immunosuppressive tumor microenvironment via GPNMB+ M2-like macrophages

Zheng Jian; Jiang Liu; Tao Ding; Shinuan Zen; Jinyang Li; Rongrong Zhong; Albert Chi-Yan Chan; Kwan Man

doi:10.1136/gutjnl-2024-IDDF.4

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a risk for hepatocellular carcinoma (HCC). The core of NAFLD pathogenesis is primarily associated with dysregulated lipid metabolism, which leads to lipid accumulation within hepatocytes. It not only contributes to lipotoxicity as a potential oncogenic evolution towards HCC, but also underpins immune evasion within the tumor microenvironment. Recent studies have identified the elongation of fatty acids, predominantly mediated by the ELOVL family of enzymes, as a contributing factor in the progression of NAFLD. Nevertheless, the implications of ELOVL activity in the transition from NAFLD to HCC are not yet fully elucidated.

Methods Mouse CRISPR/dCas9-mediated transcriptional activation library screening systems were applied to determine the key targets in the progression of NAFLD-HCC in mouse models. RNA-sequencing analysis were used to explore the crucial signalling pathway. A comprehensive analysis of ELOVL1 expression in the NAFLD-HCC local cohort were performed. DEN or transgenic TP53^KO/Myc^OE mouse with high-fat methionine-choline-deficient diet (HFMCD) induced NAFLD-HCC model were established to explore the role of ELOVL1 on tumor progression.

Results ELOVL1 was a top candidate in the NAFLD-HCC orthotopic mouse model among fatty acid elongation family by CRISPR-dCas9 screening. RNA-seq data and local clinical samples showed that ELOVL1 expression was significantly induced in NAFLD-HCC (IDDF2024-ABS-0199-Figure 1. ELOVL1 was upregulated in NAFLD HCC and crucial for NAFLD HCC progression in vivo). The increased expression of ELOVL1 was correlated with poor overall survival (OS) and less CD8⁺ T cells infiltration in the local cohort (IDDF2024-ABS-0199 Figure 2. ELOVL1 was overexpressed in NAFLD HCC with poor clinical features and less CD8 T cells infiltration). ELOVL1 knockdown could inhibit HCC growth in HFMCD-induced NAFLD-HCC models and alleviate the fibrosis level in the liver context (IDDF2024-ABS-0199 Figure 3. ELOVL1 knockdown inhibited HCC growth in HFMCD-induced NAFLD HCC models). ELOVL1 knockdown inhibited hepatocarcinogenesis and reshaped immune cells infiltration profile with less CD206⁺IL10⁺ mφ and more TNF-α/IFN-γ CD8⁺ T cells infiltration (IDDF2024-ABS-0199 Figure 4. ELOVL1 knockdown inhibited hepatocarcinogenesis and reshaped immune cells infiltration profile). Cell sorting and RNA-seq demonstrated that GPNMB⁺ mφ infiltration was the main cause of ELOVL1-promoting tumor growth (IDDF2024-ABS-0199 Figure 5. GPNMB macrophages infiltration accounted for ELOVL1-promoting tumor growth).

Conclusions ELOVL1 reshapes the immune cell profile in the tumor microenvironment with a high infiltration of GPNMB+ M2-like macrophages, which may diminish CD8+ T cell anti-tumor immunity and accelerate NAFLD-HCC progression.