Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma

Meng He, Yongxiang Liu, Song Chen, Haijing Deng, Cheng Feng, Shuang Qiao, Qifeng Chen, Yue Hu, Huiming Chen, Xun Wang, Xiongying Jiang, Xiaojun Xia, Ming Zhao () and Ning Lyu ()
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Meng He: Sun Yat-sen University Cancer Center, Guangzhou
Yongxiang Liu: Sun Yat-sen University Cancer Center, Guangzhou
Song Chen: Sun Yat-sen University Cancer Center, Guangzhou
Haijing Deng: The University of Hong Kong
Cheng Feng: Sun Yat-sen University Cancer Center, Guangzhou
Shuang Qiao: Sun Yat-sen University Cancer Center, Guangzhou
Qifeng Chen: Sun Yat-sen University Cancer Center, Guangzhou
Yue Hu: Sun Yat-sen University Cancer Center, Guangzhou
Huiming Chen: Sun Yat-sen University Cancer Center, Guangzhou
Xun Wang: Sun Yat-sen University Cancer Center, Guangzhou
Xiongying Jiang: Sun Yat-sen University Cancer Center, Guangzhou
Xiaojun Xia: Sun Yat-sen University Cancer Center, Guangzhou
Ming Zhao: Sun Yat-sen University Cancer Center, Guangzhou
Ning Lyu: Sun Yat-sen University Cancer Center, Guangzhou

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of serum amyloid A (SAA) > 20.0 mg/L has the highest accuracy in predicting anti-PD-1 resistance in HCC. Further experiments show a correlation between peritumoral SAA expression and circulating SAA levels in patients with progressive disease after PD-1 inhibition. In vitro experiments demonstrate that SAA induces neutrophils to express PD-L1 through glycolytic activation via an LDHA/STAT3 pathway and to release oncostatin M, thereby attenuating cytotoxic T cell function. In vivo, genetic or pharmacological inhibition of STAT3 or SAA eliminates neutrophil-mediated immunosuppression and enhances antitumor efficacy of anti-PD-1 treatment. This study indicates that SAA may be a critical inflammatory cytokine implicated in anti-PD-1 resistance in HCC. Targeting SAA-induced PD-L1+ neutrophils through STAT3 or SAA inhibition may present a potential approach for overcoming anti-PD1 resistance.

Date: 2024
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DOI: 10.1038/s41467-024-46118-w

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