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.

中文翻译：

---

奥沙利铂在肝细胞癌细胞中诱导免疫原性细胞死亡，并与免疫检查点阻断疗法协同作用。

背景

肝细胞癌（HCC）是最常见和最具破坏性的恶性肿瘤之一。奥沙利铂是一种基于铂的化疗药物，已被批准用于治疗多种恶性肿瘤，包括 HCC。然而，它在 HCC 中的作用尚未确定。本研究旨在研究奥沙利铂作为免疫原性细胞死亡 (ICD) 诱导剂的潜力，并探讨其对 HCC 对免疫检查点阻断疗法反应的调节作用。

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。将小鼠 HCC 细胞 (H22) 皮下接种到小鼠体内以建立同系肿瘤移植模型，然后评估肿瘤大小和体内免疫细胞活化。为了评估奥沙利铂与抗 PD-1 抗体对 H22 肿瘤的推定协同作用，量化了肿瘤参数和分泌的细胞因子。

结果

发现用奥沙利铂处理人和鼠 HCC 细胞后，ICD 相关生物标志物得到增强。此外，我们发现未成熟树突状细胞 (DC) 与奥沙利铂处理的 H22 细胞共培养后，成熟树突细胞 (DC) 的数量增加。发现体内CD8 ⁺ T 细胞和成熟 DC 的数量增加，而相反，Treg 细胞的数量减少。奥沙利铂组的肿瘤大小小于对照组。在同基因肿瘤移植模型中，我们发现奥沙利铂和抗 PD-1 抗体联合治疗可以获得比单药治疗更好的结果，如 (i) 抑制肿瘤生长和 TGF-β 分泌和 (ii) 炎症增强细胞因子分泌。

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。由奥沙利铂和免疫检查点抑制剂组成的联合疗法可能为 HCC 的治疗开辟新的途径。