Abstract | BACKGROUND AND AIM: METHODS: The anti- tumor efficacy of single-agent or combination treatment was measured by change in tumor volume and animal survival using an orthotopic liver cancer model. Distribution of T-cell subpopulations in tumor-infiltrating lymphocytes (TILs) and splenocytes derived from tumor-implanted mice was measured by flow cytometry. Depletion of relevant T-cell subpopulations or cytokines was done by co-administration of relevant antibodies with study drug treatment. Tumor cell apoptosis and tumor angiogenesis were measured by transferase deoxytidyl uridine end labeling assay and immunohistochemical study, respectively. RESULTS: Combination of sorafenib and lenalidomide produced significant synergistic anti- tumor efficacy in terms of tumor growth delay and animal survival. This synergistic effect was associated with a significant increase in interferon-γ expressing CD8(+) lymphocytes in TILs and a significantly higher number of granzyme- or perforin-expressing CD8(+) T cells, compared with vehicle- or single-agent treatment groups. Combination treatment significantly increased apoptotic tumor cells and vascular normalization in tumor tissue. The synergistic anti- tumor effect was abolished after CD8 depletion. CONCLUSIONS:
Lenalidomide can enhance the anti- tumor effects of sorafenib in HCC through its immune modulatory effects, and CD8(+) TILs play an important role in the anti- tumor synergism.
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Authors | Da-Liang Ou, Chun-Jung Chang, Yung-Ming Jeng, Yi-Jang Lin, Zhong-Zhe Lin, Anita K Gandhi, Sheng-Chieh Liao, Zi-Ming Huang, Chiun Hsu, Ann-Lii Cheng |
Journal | Journal of gastroenterology and hepatology
(J Gastroenterol Hepatol)
Vol. 29
Issue 12
Pg. 2021-31
(Dec 2014)
ISSN: 1440-1746 [Electronic] Australia |
PMID | 25160036
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. |
Chemical References |
- Antineoplastic Agents
- Immunologic Factors
- Phenylurea Compounds
- Niacinamide
- Thalidomide
- Interferon-gamma
- Sorafenib
- Lenalidomide
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- CD8-Positive T-Lymphocytes
(immunology)
- Carcinoma, Hepatocellular
(drug therapy, immunology, pathology)
- Disease Models, Animal
- Drug Synergism
- Drug Therapy, Combination
- Humans
- Immunologic Factors
(pharmacology, therapeutic use)
- Interferon-gamma
- Lenalidomide
- Liver Neoplasms
(drug therapy, immunology, pathology)
- Mice
- Niacinamide
(analogs & derivatives, pharmacology, therapeutic use)
- Phenylurea Compounds
(pharmacology, therapeutic use)
- Sorafenib
- T-Lymphocyte Subsets
- Thalidomide
(analogs & derivatives, pharmacology, therapeutic use)
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