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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Research Article Cell biology Immunology

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 6

The levels of SIRT2 and relative acetyl-K98 FGL1 are negatively correlated and predict HCC prognosis.

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The levels of SIRT2 and relative acetyl-K98 FGL1 are negatively correlat...
(A and B) Representative images of IHC staining for SIRT2, total FGL1 protein, and acetyl-K98 FGL1 in HCC and adjacent tissues (A). Scale bars: 200 μm. A total of 94 HCC cancer tissues and 86 adjacent tissues were analyzed. The IHC results were quantified and analyzed (B), and statistical differences were determined by Student’s t test. (C and D) Statistical analyses of SIRT2 and acetyl-K98/total FGL1 levels in HCC tumors of different stages. HCC tissues from 94 patients were categorized into different stages based on clinical data following AJCC classification. Statistical differences were determined by Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001. (E and F) Representative images of IHC staining for SIRT2, total FGL1 protein, and acetyl-K98 FGL1 in HCC tissues derived from 4 patients (E). Scale bars: 200 μm (left panel) and 50 μm (right panel). (F) Statistical analysis of all samples from 86 paired samples. The IHC stains were scored, and Pearson’s correlation test was used to analyze the relationship between the levels of FGL1 and SIRT2 and the levels of acetyl-K98/total FGL1 and SIRT2. Certain dots on the graphs represent more than 1 specimen and are shown as overlapping. (G) Kaplan-Meier analysis of the correlation between SIRT2 protein levels and FGL1 and acetyl-K98/total FGL1 levels and overall survival of patients with HCC in the validated cohort (n = 94) with high and low expression of SIRT2, FGL1, and acetyl-K98/total FGL1. Cutoff values between groups with high and low expression were determined using the median value according to the total score obtained by combining the proportion and intensity scores. P values in G were calculated using the log-rank test. (H) Forest plot of multivariate analyses. See also Supplemental Table 7.