Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
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 experiment...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46118-w |
| _version_ | 1797274130674876416 |
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| author | 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 Ning Lyu |
| author_facet | 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 Ning Lyu |
| author_sort | Meng He |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:53:58Z |
| format | Article |
| id | doaj.art-de91ee4513664ee88d2c7da1981cba94 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:53:58Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-de91ee4513664ee88d2c7da1981cba942024-03-05T19:32:36ZengNature PortfolioNature Communications2041-17232024-02-0115111910.1038/s41467-024-46118-wSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinomaMeng He0Yongxiang Liu1Song Chen2Haijing Deng3Cheng Feng4Shuang Qiao5Qifeng Chen6Yue Hu7Huiming Chen8Xun Wang9Xiongying Jiang10Xiaojun Xia11Ming Zhao12Ning Lyu13State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouDepartment of Pathology, The University of Hong KongState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouState Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, GuangzhouAbstract 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.https://doi.org/10.1038/s41467-024-46118-w |
| spellingShingle | 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 Ning Lyu Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma Nature Communications |
| title | Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma |
| title_full | Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma |
| title_fullStr | Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma |
| title_full_unstemmed | Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma |
| title_short | Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma |
| title_sort | serum amyloid a promotes glycolysis of neutrophils during pd 1 blockade resistance in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41467-024-46118-w |
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