Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.
J Immunother Cancer. 2020 Nov;8(2). doi: 10.1136/jitc-2020-001367.
Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis.
The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated.
In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages.
The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.
胰腺导管腺癌 (PDAC) 是最可怕的恶性肿瘤之一，部分原因是缺乏有效的化疗药物。免疫检查点抑制剂，包括抗程序性细胞死亡 1（抗 PD-1）抗体，是一种新型的有前途的系统免疫疗法。在本研究中，我们使用肝转移的小鼠模型评估吉西他滨 (GEM) 联合抗 PD-1 抗体治疗作为晚期 PDAC 的免疫化疗是否有效。
通过向免疫功能正常的 C57BL/6J 小鼠脾内注射小鼠胰腺癌细胞系 PAN02 建立 PDAC 肝转移的小鼠模型。用抗 PD-1 抗体、GEM 或 GEM 联合抗 PD-1 抗体治疗小鼠，并与未治疗（对照组）进行比较；研究了肝转移、免疫细胞浸润、基因表达、免疫细胞反应表型和总生存期。
在 GEM 联合抗 PD-1 抗体治疗的转移性肿瘤组织中，我们观察到 Th1 淋巴细胞和 M1 巨噬细胞浸润增加。对 GEM 联合抗 PD-1 抗体治疗的小鼠外周血细胞的基因表达谱分析清楚地突出了 T 细胞和先天免疫信号通路。与 GEM 单独治疗（中位生存期 56 天）相比，GEM 联合抗 PD-1 抗体治疗显著延长了 PDAC 肝转移小鼠的生存期（中位生存期 66 天）。从 GEM 联合抗 PD-1 抗体治疗的 PDAC 肝转移小鼠的脾淋巴细胞中分离出的扩增淋巴细胞，其 M1 巨噬细胞数量增加。
抗 PD-1 抗体免疫疗法联合 GEM 通过增强 Th1 淋巴细胞和 M1 巨噬细胞介导的免疫反应，并与 CD8+T 细胞相关，有利于治疗 PDAC 肝转移的小鼠模型。
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