Department of Pharmacy, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Int J Oncol. 2018 Jun;52(6):2079-2092. doi: 10.3892/ijo.2018.4358. Epub 2018 Apr 4.
Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. Research investigating novel therapeutic strategies for the treatment of HCC is urgently required. Monoclonal antibodies (mAbs) that target the programmed cell death‑1 (PD‑1/PDCD1)/programmed death-ligand 1 (PD-L1) immune checkpoint have demonstrated substantial clinical benefit for a variety of solid tumors; however, these mAbs have not been well studied in HCC. In the present study, Sp2/0-Ag14 myeloma cells and spleen cells derived from BALB/c mice immunized with the recombinant human PD‑1/PDCD1 protein were fused for the production of novel antibodies. The 9E11 mAb, which exhibited the highest specificity for PD‑1 in HCC tissues in western blot and immunohistochemical staining analyses, was used to investigate the clinical significance of PD‑1 expression in HCC tissues from 77 cases, which were collected and examined histologically. Overexpression of PD‑1 was identified in peritumoral tissues, primarily in the liver portal region. Importantly, by analyzing the clinical data from 77 HCC patients, the expression of PD‑1 was observed to be significantly correlated with larger tumor size (>5 cm) and poorly differentiated tumors. In addition, PD‑1 expression was moderately correlated with venous thrombosis, but not correlated with patient sex or age, liver cirrhosis, hepatitis B, tumor, node and metastasis (TNM) stage or tumor location. The results of the present study suggest that high-level PD‑1 expression may be an important factor associated with the immune checkpoint pathway in HCC. The results suggest that PD‑1 serves an important role in tumor immune evasion and may be a valuable immunodiagnostic marker. In addition, PD‑1 may serve as a therapeutic target for patients presenting with poorly differentiated HCC, thus indicating the potential application of a PD‑1 inhibitor for the treatment of HCC patients.
肝细胞癌（HCC）是全球最常见的恶性肿瘤和死亡原因之一。迫切需要研究治疗 HCC 的新型治疗策略。针对程序性细胞死亡-1（PD-1/PDCD1）/程序性死亡配体 1（PD-L1）免疫检查点的单克隆抗体（mAb）已在多种实体瘤中显示出显著的临床获益；然而，这些 mAb 在 HCC 中的研究还不够充分。在本研究中，用重组人 PD-1/PDCD1 蛋白免疫的 Sp2/0-Ag14 骨髓瘤细胞和 BALB/c 小鼠的脾细胞融合，以生产新型抗体。9E11 mAb 在 Western blot 和免疫组织化学染色分析中对 HCC 组织中的 PD-1 具有最高的特异性，用于研究 77 例 HCC 组织中 PD-1 表达的临床意义，这些组织均经过组织学检查。在肿瘤周围组织中，主要在肝门区域，鉴定出 PD-1 的过表达。重要的是，通过分析 77 例 HCC 患者的临床数据，观察到 PD-1 的表达与肿瘤较大（>5cm）和分化较差的肿瘤显著相关。此外，PD-1 表达与静脉血栓形成中度相关，但与患者性别或年龄、肝硬化、乙型肝炎、肿瘤、淋巴结和转移（TNM）分期或肿瘤位置无关。本研究的结果表明，高水平的 PD-1 表达可能是 HCC 中免疫检查点途径的一个重要因素。结果表明，PD-1 在肿瘤免疫逃逸中起重要作用，可能是一种有价值的免疫诊断标志物。此外，PD-1 可能作为分化差的 HCC 患者的治疗靶点，因此表明 PD-1 抑制剂可能应用于 HCC 患者的治疗。
