Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.
摘要：
目标：原发性肝癌，特别是肝细胞癌（HCC），这是一个巨大的全球卫生挑战。虽然免疫检查点抑制剂在肝癌治疗中是有效的，一些患者仍经历疾病进展。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，并确定了吉西他滨在治疗HCC中的潜在治疗作用。
方法：基于流体动力学的转染，采用睡美人转座酶系统，递送替代肿瘤抗原，NRAS（NRAS原癌基因，GTPase),ShP53和SB100给C57BL/6小鼠。建立了基本的HCC小鼠模型。测试无病原体动物的血清和肝毒性。使用丙氨酸转氨酶和天冬氨酸转氨酶水平监测HCC预后。进行肝脏组织学免疫组织化学和小鼠脾细胞/肝内免疫细胞流式细胞术。评估人和小鼠血清中的IL-1β水平。
结果：与非HCC对照组相比，HCC患者的白细胞介素-1β水平升高。肝癌小鼠模型肝IL-1β水平高于非肝癌小鼠，提示肝脏局部炎症。IL-1受体1型（IL-1R1）敲除（IL-1R1-/-）小鼠表现出比野生型小鼠更严重的HCC进展，尽管肝内IL-1β浓度高。IL-1R1-/-小鼠表现出髓源性抑制细胞和调节性T细胞的肝脏水平增加，这可能会加剧肝癌。吉西他滨显著降低HCC肿瘤负荷，改善肝脏状况，并提高肝癌小鼠模型的生存率。吉西他滨降低骨髓来源的抑制细胞和调节性T细胞的肝脏水平，可能减轻肝脏的免疫抑制。
结论：靶向IL-1或吉西他滨联合免疫治疗是治疗晚期HCC的有希望的方法。
方法：基于流体动力学的转染，采用睡美人转座酶系统，递送替代肿瘤抗原，NRAS（NRAS原癌基因，GTPase),ShP53和SB100给C57BL/6小鼠。建立了基本的HCC小鼠模型。测试无病原体动物的血清和肝毒性。使用丙氨酸转氨酶和天冬氨酸转氨酶水平监测HCC预后。进行肝脏组织学免疫组织化学和小鼠脾细胞/肝内免疫细胞流式细胞术。评估人和小鼠血清中的IL-1β水平。
结果：与非HCC对照组相比，HCC患者的白细胞介素-1β水平升高。肝癌小鼠模型肝IL-1β水平高于非肝癌小鼠，提示肝脏局部炎症。IL-1受体1型（IL-1R1）敲除（IL-1R1-/-）小鼠表现出比野生型小鼠更严重的HCC进展，尽管肝内IL-1β浓度高。IL-1R1-/-小鼠表现出髓源性抑制细胞和调节性T细胞的肝脏水平增加，这可能会加剧肝癌。吉西他滨显著降低HCC肿瘤负荷，改善肝脏状况，并提高肝癌小鼠模型的生存率。吉西他滨降低骨髓来源的抑制细胞和调节性T细胞的肝脏水平，可能减轻肝脏的免疫抑制。
结论：靶向IL-1或吉西他滨联合免疫治疗是治疗晚期HCC的有希望的方法。
