Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma
Mingen Lin, … , Yanping Xu, Lei Lv
Mingen Lin, … , Yanping Xu, Lei Lv
Published May 1, 2023
Citation Information: J Clin Invest. 2023;133(9):e164528. https://doi.org/10.1172/JCI164528.
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Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma

Abstract

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.

Authors

Mingen Lin, Jing He, Xinchao Zhang, Xue Sun, Wenjing Dong, Ruonan Zhang, Yanping Xu, Lei Lv

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Figure 5

Aspirin downregulates FGL1 and enhances the efficacy of anti–PD-L1 immunotherapy.

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Aspirin downregulates FGL1 and enhances the efficacy of anti–PD-L1 immun...
(A) Schematic representation of the experimental procedure. (B) Representative tumors in C57BL/6 mice injected s.c. with Hepa 1-6 cells from different groups with control, anti–PD-L1 mAb, aspirin, or combined treatment, respectively. (C) Tumor growth of Hepa 1-6 cells in C57BL/6 mice treated with control (black lines), aspirin (red lines), anti–PD-L1 mAb (blue lines), or their combination (green lines). n = 7 biologically independent animals per group. Tumor growth is shown as the mean tumor diameter ± SD. (D) Kaplan-Meier survival curves for each treatment group (G1, G2, G3, G4). n = 7 biologically independent animals per group. p values were calculated using a 2-sided Gehan-Breslow-Wilcoxon test. (E) IB analysis of FGL1 and FGL2 protein levels in Hepa 1-6 tumor tissues from each group with GAPDH as the internal control. (F) IHC analysis of CD8+ T cell infiltration and granzyme B expression in the Hepa 1-6 tumor mass as indicated. Scale bars: 100 μm. Data represent the mean ± SD of 5 independent samples from each group. (G) IHC results from F were quantified, and the statistical differences were determined by Bonferroni-adjusted P values. *P < 0.05, **P < 0.01, and ***P < 0.001, with raw P values derived from an unpaired Student’s t test.