Fatty acid desaturase 1 mediating metabolic reprogramming of polyunsaturated fatty acids promotes HCC progression by impairing CD8+ T cell anti-tumor immunity

Abstract

<p><strong>Background</strong> Aberrant polyunsaturated fatty acids (PUFAs) metabolism is a novel characterization of hepatocellular carcinoma (HCC), closely associated with immunosuppression. A rate-limiting enzyme controlling PUFAs biosynthesis, especially arachidonic acid (ARA) production from dihomo-γ-linolenic acid (DGLA), fatty acid desaturase 1 (FADS1) is overexpressed in HCC. Here, we aim to investigate the interaction of metabolic function of FADS1 with the HCC microenvironment in promoting tumor progression and the translational potentials in clinical applications.</p><p><strong>Methods</strong> Firstly, tissue interstitial fluids (TIFs) were isolated and analyzed from fresh paired adjacent tissues and HCC (n=9) for detecting the PUFAs alterations in the HCC microenvironment. Integrated analyses were performed in multiple public databases and local cohorts. Then, the CD8⁺ T cell apoptosis was examined after being cultured with ARA. Next, Fads1 knockdown (KD) hepa1–6 HCC cell line was generated by CRISPRi to observe the tumor biology and metabolic function. Liver-specific Fads1 knockout (Fads1 KO) mice and Fads1 transgenic (Fads1 tg) mice were established to determine the interplay of FADS1 with CD8⁺ T cell anti-tumor immunity. Finally, FADS1 expression was evaluated in non-responses and responses HCC patients who received anti-PD-1 treatment from our clinical trial.</p><p><strong>Results</strong> Clinically, the PUFAs metabolomics showed that the ARA level was upregulated in HCC TIFs (IDDF2022-ABS-0261 Figure 1). High expression of FADS1 predicted poor survival and was negatively correlated with CD8⁺ T cells infiltration, as well as the enrichment of T cells mediated cytotoxicity and activation in HCC patients (IDDF2022-ABS-0261 Figure 2). Functionally, supplemented ARA induced CD8⁺ T cell apoptosis (IDDF2022-ABS-0261 Figure 3). Fads1 KD did not affect the HCC cell proliferation, but the ARA level was decreased in the conditional medium (data not shown). Fads1 KO inhibited the HCC development via elevating CD8⁺ T cell infiltration in the tumor region (IDDF2022-ABS-0261 Figure 4), while Fads1 Tg promoted HCC progression by restraining immune surveillance (IDDF2022-ABS-0261 Figure 5) (IDDF2022-ABS-0261 Table 1). Additionally, the expression of FADS1 was downregulated in response patients with anti-PD-1 treatment (IDDF2022-ABS-0261 Figure 6).</p>