Ph.D. Program of Interdisciplinary Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Ever Health Clinic, Taichung, Taiwan.
J Gastroenterol Hepatol. 2024 Oct;39(10):2208-2218. doi: 10.1111/jgh.16674. Epub 2024 Jul 15.
Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC.
Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1β levels in human and mouse serum were assessed.
Interleukin-1β levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1β levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1β concentration. IL-1R1 mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver.
Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.
原发性肝癌，特别是肝细胞癌（HCC），是一个重大的全球健康挑战。尽管免疫检查点抑制剂在 HCC 治疗中有效，但仍有部分患者发生疾病进展。白细胞介素-1（IL-1）调节免疫和炎症。我们研究了 IL-1 在 HCC 发展和进展中的作用，并确定了吉西他滨治疗 HCC 的潜在治疗作用。
采用睡美人转座酶系统的流体动力学转染，将替代肿瘤抗原 NRAS（NRAS 原癌基因，GTP 酶）、ShP53 和 SB100 递送至 C57BL/6 小鼠。建立了基本的 HCC 小鼠模型。对无菌动物进行血清和肝毒性检测。通过丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平监测 HCC 预后。进行肝组织学免疫组化和小鼠脾/肝内免疫细胞流式细胞术检测。评估人血清和小鼠血清中 IL-1β 水平。
与非 HCC 对照组相比，HCC 患者的 IL-1β 水平升高。HCC 小鼠模型的肝内 IL-1β 水平高于非 HCC 小鼠，提示局部肝内炎症。与野生型小鼠相比，IL-1 受体 1（IL-1R1）敲除（IL-1R1）小鼠的 HCC 进展程度较轻，尽管肝内 IL-1β 浓度较高。IL-1R1 小鼠的肝内髓系来源抑制细胞和调节性 T 细胞水平升高，可能加重 HCC。吉西他滨显著降低 HCC 肿瘤负担，改善肝状况，提高 HCC 小鼠模型的存活率。吉西他滨降低了肝内髓系来源抑制细胞和调节性 T 细胞水平，可能减轻肝内免疫抑制。
靶向 IL-1 或联合吉西他滨与免疫疗法是治疗晚期 HCC 的一种有前途的方法。
