Potential synergistic anti-tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma
Journal
Journal of Gastroenterology and Hepatology (Australia)
Journal Volume
29
Journal Issue
12
Pages
2021-2031
Date Issued
2014
Author(s)
Chang C.-J.
Lin Y.-J.
Gandhi A.K.
Liao S.-C.
Huang Z.-M.
Abstract
Background and Aim: The immune modulatory drug lenalidomide has shown promising anti-tumor activity in a clinical trial of patients with advanced hepatocellular carcinoma (HCC). The present study explored whether lenalidomide can enhance the anti-tumor activity of sorafenib, the standard molecular targeted therapy for HCC. 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. ? 2014 Wiley Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation.
SDGs
Other Subjects
alpha actin; collagen type 4; gamma interferon; granzyme; granzyme B; Ki 67 antigen; lenalidomide; perforin; sorafenib; antineoplastic agent; carbanilamide derivative; gamma interferon; immunologic factor; lenalidomide; nicotinamide; sorafenib; thalidomide; animal cell; animal experiment; animal model; animal tissue; antiangiogenic activity; antineoplastic activity; apoptosis; Article; breast cancer cell line; cancer combination chemotherapy; cancer growth; cancer inhibition; cancer size; cancer survival; CD8+ T lymphocyte; cell count; cell disruption; cell stimulation; cell viability; controlled study; cytotoxicity; drug effect; drug efficacy; drug megadose; drug potentiation; drug tolerability; granulocytosis; human; human cell; immunomodulation; in vitro study; in vivo study; leukocytosis; liver cancer cell line; liver carcinogenesis; liver cell carcinoma; low drug dose; lymphocyte count; lymphocytosis; molecularly targeted therapy; monotherapy; mouse; nonhuman; priority journal; protein expression; regulatory T lymphocyte; spleen cell; T cell depletion; T lymphocyte subpopulation; treatment duration; tumor associated leukocyte; tumor microenvironment; upregulation; analogs and derivatives; animal; Carcinoma, Hepatocellular; disease model; drug combination; drug potentiation; immunology; Liver Neoplasms; pathology; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Immunologic Factors; Interferon-gamma; Liver Neoplasms; Mice; Niacinamide; Phenylurea Compounds; T-Lymphocyte Subsets; Thalidomide
Publisher
Blackwell Publishing
Type
journal article