Oncotarget

Research Papers:

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 and Jinsil Seong

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Oncotarget. 2017; 8:41242-41255. https://doi.org/10.18632/oncotarget.17168

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Abstract

Kyoung-Jin Kim1, Ji-Hye Kim1, Seo Jin Lee1, Eun-Jung Lee1, Eui-Cheol Shin2 and Jinsil Seong1

1Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea

2Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Techonology, Daejeon, Republic of Korea

Correspondence to:

Jinsil Seong, email: jsseong@yuhs.ac

Keywords: hepatocellular carcinoma, anti-PD-L1, radiation, combination therapy, antitumor effect

Received: October 21, 2016     Accepted: March 28, 2017     Published: April 17, 2017

ABSTRACT

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.


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