Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

Autor: Chu CS; Ph.D. Program of Interdisciplinary Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.; Ever Health Clinic, Taichung, Taiwan., Chen HP; Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.; Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan., Lin PH; Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan., Cheng CC; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan., Kuo HY; Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan., Fan PH; Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan., Peng WH; School of Medicine, Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan., Wu LL; Health Innovation Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.; Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.; Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Jazyk: angličtina
Zdroj: Journal of gastroenterology and hepatology [J Gastroenterol Hepatol] 2024 Oct; Vol. 39 (10), pp. 2208-2218. Date of Electronic Publication: 2024 Jul 15.
DOI: 10.1111/jgh.16674
Abstrakt: Background and Aim: 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.
(© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
Databáze: MEDLINE
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