奥沙利铂诱导肝癌细胞发生免疫原性细胞死亡，并与免疫检查点阻断治疗协同作用。
Oxaliplatin induces immunogenic cell death in hepatocellular carcinoma cells and synergizes with immune checkpoint blockade therapy.
机构信息
Department of Hepatopancreatobiliary Surgery, Hangzhou First People's Hospital, the Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, 310006, Zhejiang, China.
Department of Gastrointestinal Surgery, Hangzhou First People's Hospital, the Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, 310006, Zhejiang, China.
出版信息
Cell Oncol (Dordr). 2020 Dec;43(6):1203-1214. doi: 10.1007/s13402-020-00552-2. Epub 2020 Aug 14.
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most common and devastating malignancies. Oxaliplatin, a platinum-based chemotherapeutic agent, is approved for the treatment of several malignancies, including HCC. However, its role in HCC is not well established. This study was designed to investigate the potential of oxaliplatin as an immunogenic cell death (ICD) inducer and to explore its regulatory effects on the response of HCC to immune checkpoint blockade therapy.
METHODS
Murine and human HCC cells were treated with oxaliplatin, followed by evaluation of the expression of ICD-related biomarkers. Murine HCC cells (H22) were subcutaneously inoculated into mice to establish a syngeneic tumor graft model, after which tumor sizes and in vivo immune cell activation were evaluated. To assess putative synergistic effects of oxaliplatin with anti-PD-1 antibodies on H22 tumors, tumor parameters and secreted cytokines were quantified.
RESULTS
ICD-related biomarkers were found to be enhanced after treatment of human and murine HCC cells with oxaliplatin. Additionally, we found that the number of mature dendritic cells (DCs) was increased after immature DCs were cocultured with oxaliplatin-treated H22 cells. The numbers of CD8 T cells and mature DCs were found to be increased in vivo whereas, in contrast, the number of Treg cells was decreased. The tumor sizes were smaller in the oxaliplatin group than in the control group. In the syngeneic tumor graft model, we found that combination therapy with oxaliplatin and anti-PD-1 antibodies could achieve better outcomes than monotherapy, as indicated by (i) inhibition of tumor growth and TGF-β secretion and (ii) augmentation of inflammatory cytokine secretion.
CONCLUSIONS
Our data indicate that oxaliplatin can be used as an inducer of ICD and as a modulator of the tumor immune microenvironment. Combination therapies composed of oxaliplatin and immune checkpoint inhibitors may open up novel avenues for the treatment of HCC.
背景
肝细胞癌（HCC）是最常见和最具破坏性的恶性肿瘤之一。奥沙利铂是一种铂类化疗药物，已被批准用于治疗多种恶性肿瘤，包括 HCC。然而，其在 HCC 中的作用尚未得到充分确立。本研究旨在探讨奥沙利铂作为免疫原性细胞死亡（ICD）诱导剂的潜力，并探索其对 HCC 对免疫检查点阻断治疗反应的调节作用。
方法
用奥沙利铂处理鼠和人 HCC 细胞，然后评估 ICD 相关生物标志物的表达。将鼠 HCC 细胞（H22）皮下接种到小鼠中，建立同源肿瘤移植模型，然后评估肿瘤大小和体内免疫细胞激活情况。为了评估奥沙利铂与抗 PD-1 抗体对 H22 肿瘤的潜在协同作用，定量分析了肿瘤参数和分泌的细胞因子。
结果
奥沙利铂处理人源和鼠源 HCC 细胞后，发现 ICD 相关生物标志物增强。此外，我们发现不成熟树突状细胞（DC）与奥沙利铂处理的 H22 细胞共培养后，成熟 DC 的数量增加。体内 CD8 T 细胞和成熟 DC 的数量增加，而 Treg 细胞的数量减少。奥沙利铂组的肿瘤体积小于对照组。在同源肿瘤移植模型中，我们发现奥沙利铂与抗 PD-1 抗体联合治疗比单独治疗效果更好，表现在（i）抑制肿瘤生长和 TGF-β分泌，以及（ii）增强炎症细胞因子分泌。
结论
我们的数据表明，奥沙利铂可用作 ICD 的诱导剂和肿瘤免疫微环境的调节剂。奥沙利铂和免疫检查点抑制剂的联合治疗可能为 HCC 的治疗开辟新途径。
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