Yuta Kimura1, Ryouichi Tsunedomi2, Kiyoshi Yoshimura3, Satoshi Matsukuma1, Yoshitaro Shindo1, Hiroto Matsui1, Yukio Tokumitsu1, Shin Yoshida1, Michihisa Iida1, Nobuaki Suzuki1, Shigeru Takeda1, Tatsuya Ioka4, Shoichi Hazama5, Hiroaki Nagano1. 1. Department of Gastroenterological, Breast, and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. 2. Department of Gastroenterological, Breast, and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. tsune-r@yamaguchi-u.ac.jp. 3. Department of Clinical Research in Tumor Immunology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Shinagawa, Tokyo, Japan. 4. Oncology Center, Yamaguchi University Hospital, Ube, Yamaguchi, Japan. 5. Department of Translational Research and Developmental Therapeutics Against Cancer, Faculty of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
Abstract
BACKGROUND: Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated. METHODS: Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing. RESULTS: The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells. CONCLUSION: Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.
BACKGROUND: Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated. METHODS: Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing. RESULTS: The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells. CONCLUSION: Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.
Authors: John Bridgewater; Peter R Galle; Shahid A Khan; Josep M Llovet; Joong-Won Park; Tushar Patel; Timothy M Pawlik; Gregory J Gores Journal: J Hepatol Date: 2014-03-27 Impact factor: 25.083
Authors: Nuh N Rahbari; Arianeb Mehrabi; Nathan M Mollberg; Sascha A Müller; Moritz Koch; Markus W Büchler; Jürgen Weitz Journal: Ann Surg Date: 2011-03 Impact factor: 12.969
Authors: Suzanne L Topalian; F Stephen Hodi; Julie R Brahmer; Scott N Gettinger; David C Smith; David F McDermott; John D Powderly; Richard D Carvajal; Jeffrey A Sosman; Michael B Atkins; Philip D Leming; David R Spigel; Scott J Antonia; Leora Horn; Charles G Drake; Drew M Pardoll; Lieping Chen; William H Sharfman; Robert A Anders; Janis M Taube; Tracee L McMiller; Haiying Xu; Alan J Korman; Maria Jure-Kunkel; Shruti Agrawal; Daniel McDonald; Georgia D Kollia; Ashok Gupta; Jon M Wigginton; Mario Sznol Journal: N Engl J Med Date: 2012-06-02 Impact factor: 91.245