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Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model

 Kyoung-Jin Kim  ;  Ji-Hye Kim  ;  Seo Jin Lee  ;  Eun-Jung Lee  ;  Eui-Cheol Shin  ;  Jinsil Seong 
 ONCOTARGET , Vol.8(25) : 41242-41255, 2017 
Journal Title
Issue Date
Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use* ; B7-H1 Antigen/antagonists & inhibitors ; B7-H1 Antigen/immunology ; B7-H1 Antigen/metabolism ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/therapy* ; Cell Line, Tumor ; Combined Modality Therapy ; Hep G2 Cells ; Humans ; Immunotherapy/methods ; Liver Neoplasms, Experimental/immunology ; Liver Neoplasms, Experimental/metabolism ; Liver Neoplasms, Experimental/therapy* ; Male ; Mice, Inbred C3H ; Radiotherapy/methods ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Signal Transduction/radiation effects ; Survival Analysis ; Tumor Burden/drug effects ; Tumor Burden/immunology ; Tumor Burden/radiation effects
anti-PD-L1 ; antitumor effect ; combination therapy ; hepatocellular carcinoma ; radiation
BACKGROUND & AIMS: Although immunotherapy has emerged as an attractive therapy for refractory cancers, its limited efficacy in hepatocellular carcinoma (HCC) suggests the need for a combination strategy that can either enhance or complement therapeutic effect. We investigated whether combination of immune checkpoint blockade (ICB) and radiation could enhance antitumor effect in a murine HCC model. METHODS: Using murine HCC, HCa-1, the effect of radiation on programmed death-ligand1 (PD-L1) expression was determined by real-time PCR, flow cytometry, and western blotting. Signaling pathways involved in altered PD-L1 expression were examined. Tumor growth and survival rate were evaluated for a combination of anti-PD-L1 and radiation. Immunological parameters in the tumor were assessed using flow cytometry and histological study. RESULTS: Radiation upregulated PD-L1 expression in tumor cells through IFN-γ/STAT3 signaling, which could facilitate therapeutic action of anti-PD-L1. Combination of anti-PD-L1 and radiation significantly suppressed tumor growth compared to treatment with anti-PD-L1 alone or radiation alone group (P<0.01). Survival was significantly improved in the combination group compared to anti-PD-L1 alone or radiation alone group (7-week survival rate; 90% vs. 0% or 30%, respectively, P<0.001). The underlying mechanism involved increasing apoptosis, decreasing tumor cell proliferation, as well as restoration of CD8+ T cell functions. CONCLUSIONS: The combination of anti-PD-L1 and radiation significantly improved the antitumor effect shown in tumor growth delay as well as in survival, supporting a novel combination strategy of immunoradiotherapy in HCC.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Seong, Jin Sil(성진실) ORCID logo https://orcid.org/0000-0003-1794-5951
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