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

Publisher: Blackwell Scientific Publications Country of Publication: Australia NLM ID: 8607909 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1440-1746 (Electronic) Linking ISSN: 08159319 NLM ISO Abbreviation: J Gastroenterol Hepatol Subsets: MEDLINE

Original Publication: Melbourne ; Boston : Blackwell Scientific Publications, c1986-

Carcinoma, Hepatocellular*/immunology ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/genetics ; Gemcitabine* ; Interleukin-1beta*/metabolism ; Liver Neoplasms*/pathology ; Liver Neoplasms*/immunology ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/genetics; Animals ; Humans ; Male ; Mice ; Antimetabolites, Antineoplastic/therapeutic use ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/therapeutic use ; Deoxycytidine/pharmacology ; Disease Models, Animal ; Disease Progression ; Liver/pathology ; Liver/metabolism ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells/immunology ; Proto-Oncogene Mas ; Receptors, Interleukin-1 Type I/genetics

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.)

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108-2320-B-010-045-MY3 National Science and Technology Council; 110-2320-B-002-080-MY3 National Science and Technology Council; 111-2314-B-A49-072 National Science and Technology Council; 112-2314-B-A49-028-MY3 National Science and Technology Council; 112-2740-B-A49-002 National Science and Technology Council; 113-2740-B-A49-003- National Science and Technology Council; 113-2321-B-A49-014- National Science and Technology Council; 113-TDU-B-221-13400 Ministry of Health and Welfare; 11210 Ministry of Health and Welfare; CI-110-22 Yen Tjing Ling Medical Foundation; CI-111-24 Yen Tjing Ling Medical Foundation; PTH110001 TYGH-NYCU Joint Research Program

Keywords: IL‐1R1; T regulatory cells; gemcitabine; hepatocellular carcinoma; myeloid‐derived suppressor cells

0 (Antimetabolites, Antineoplastic)
0W860991D6 (Deoxycytidine)
0 (Gemcitabine)
0 (Interleukin-1beta)
0 (MAS1 protein, human)
0 (Proto-Oncogene Mas)
0 (Receptors, Interleukin-1 Type I)

Date Created: 20240715 Date Completed: 20241008 Latest Revision: 20241018

20241019

10.1111/jgh.16674

39005010