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自体扩增自然杀伤细胞联合程序性死亡蛋白1抑制剂改善腹膜转移性胰腺癌腹水免疫微环境:一项病例研究

Autologous expanded NK cells combined with PD-1 inhibitor improved ascitic fluid immune microenvironment of peritoneal metastatic pancreatic cancer: a case study.

作者信息

Chen Ling, Qian Yuping, Guo Meng, Liu Yanfang, Li Jie, Wu Meihong, Zhang Yingyi, Wang Yujie, Peng Xiaobo, Zhan Xianbao

机构信息

Department of Oncology, Changhai Hospital, Naval Medical University Shanghai, People's Republic of China.

Department of Pathology, Changhai Hospital, Naval Medical University Shanghai, People's Republic of China.

出版信息

Am J Transl Res. 2023 Jan 15;15(1):316-323. eCollection 2023.

Abstract

The presence of peritoneal metastasis in patients with pancreatic cancer is associated with poor prognosis. Chemotherapy and radiotherapy may result in poor prognosis in patients with pancreatic cancer. However, immunotherapy improves prognosis even at an advanced stage of the disease. The present study reported a case of a combined therapy of autologous expanded natural killer (NK) cells and programmed cell death 1 (PD-1) inhibitor in a patient with pancreatic cancer and peritoneal metastasis. The NK cells were expanded and intravenously injected. This was followed by intravenous administration of two dosages of PD-1 inhibitor. Computed tomography and magnetic resonance imaging were performed to assess the size of tumor before and after the combined therapy. In addition, the blood sample and ascites were collected and analyzed before and after the combined therapy. Flow cytometry was carried out to measure the subsets of T cells and macrophages in the collected ascites. Meanwhile, the levels of cytokines in the ascites were quantified through enzyme-linked immunosorbent assay, and Luminex assays were conducted on the supernatant. It was revealed that after the combined therapy, cancer cells disappeared in the ascites, and the T cells were activated, which could be confirmed by the decreased levels of PD-1 and T cell immunoglobulin and mucin domain-containing protein 3. Also, the functioning of macrophages was improved, as shown by the increased level of CD86 and the reduced levels of CD206 and HLA-DR. Notably, the levels of cytokines (transforming growth factor-β, vascular endothelial growth factor, and interleukin-10) in ascites were significantly upregulated after the combined therapy. In conclusion, it was evident that NK cells combined with PD-1 inhibitor improved the immune microenvironment of carcinomatosis in the peritoneal cavity. Therefore, the combined therapy may be beneficial for suppressing pancreatic cancer and the presence of metastases in the peritoneal cavity. However, there is a need for additional randomized studies to confirm the efficacy of combined therapy.

摘要

胰腺癌患者出现腹膜转移与预后不良相关。化疗和放疗可能导致胰腺癌患者预后不良。然而,免疫疗法即使在疾病晚期也能改善预后。本研究报告了1例胰腺癌伴腹膜转移患者接受自体扩增自然杀伤(NK)细胞与程序性细胞死亡蛋白1(PD-1)抑制剂联合治疗的病例。NK细胞经扩增后静脉注射。随后静脉给予两剂PD-1抑制剂。在联合治疗前后进行计算机断层扫描和磁共振成像以评估肿瘤大小。此外,在联合治疗前后采集血样和腹水并进行分析。采用流式细胞术检测所采集腹水中T细胞和巨噬细胞亚群。同时,通过酶联免疫吸附测定对腹水中细胞因子水平进行定量,并对上清液进行Luminex检测。结果显示,联合治疗后腹水中癌细胞消失,T细胞被激活,这可通过PD-1以及T细胞免疫球蛋白和粘蛋白结构域包含蛋白3水平降低得到证实。此外,巨噬细胞功能得到改善,表现为CD86水平升高,CD206和HLA-DR水平降低。值得注意的是,联合治疗后腹水中细胞因子(转化生长因子-β、血管内皮生长因子和白细胞介素-10)水平显著上调。总之,显然NK细胞与PD-1抑制剂联合改善了腹膜腔癌转移的免疫微环境。因此,联合治疗可能有助于抑制胰腺癌及腹膜腔转移灶的存在。然而,需要更多的随机研究来证实联合治疗的疗效。

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