State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Nat Commun. 2024 Feb 26;15(1):1754. doi: 10.1038/s41467-024-46118-w.
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.
程序性死亡受体-1（PD-1）阻断在肝细胞癌（HCC）中的反应各不相同。我们利用 16 种血清因子的组合表明，血清淀粉样蛋白 A（SAA）的循环水平>20.0mg/L 具有预测 HCC 抗 PD-1 耐药的最高准确性。进一步的实验表明，在 PD-1 抑制后疾病进展的患者中，肿瘤周围 SAA 表达与循环 SAA 水平之间存在相关性。体外实验表明，SAA 通过通过 LDHA/STAT3 途径诱导糖酵解激活使中性粒细胞表达 PD-L1，并释放致癌素 M，从而削弱细胞毒性 T 细胞的功能。在体内，通过遗传或药理学抑制 STAT3 或 SAA 可消除中性粒细胞介导的免疫抑制作用，并增强抗 PD-1 治疗的抗肿瘤疗效。这项研究表明，SAA 可能是 HCC 中抗 PD-1 耐药性的关键炎症细胞因子。通过 STAT3 或 SAA 抑制靶向 SAA 诱导的 PD-L1 中性粒细胞可能是克服抗 PD1 耐药的一种潜在方法。
