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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 deathligand1 (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.

Original languageEnglish
Pages (from-to)41242-41255
Number of pages14
JournalOncotarget
Volume8
Issue number25
DOIs
Publication statusPublished - 2017 Jan 1

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Hepatocellular Carcinoma
Radiation
Neoplasms
Flow Cytometry
Growth
Radioimmunotherapy
Radiation Effects
Therapeutic Uses
Immunotherapy
Real-Time Polymerase Chain Reaction
Therapeutics
Western Blotting
Cell Proliferation
Apoptosis
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Kim, Kyoung Jin ; Kim, Ji Hye ; Lee, Seo Jin ; Lee, Eun Jung ; Shin, Eui Cheol ; Seong, Jinsil. / Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model. In: Oncotarget. 2017 ; Vol. 8, No. 25. pp. 41242-41255.
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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 deathligand1 (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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Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model. / Kim, Kyoung Jin; Kim, Ji Hye; Lee, Seo Jin; Lee, Eun Jung; Shin, Eui Cheol; Seong, Jinsil.

In: Oncotarget, Vol. 8, No. 25, 01.01.2017, p. 41242-41255.

Research output: Contribution to journalArticle

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AB - 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 deathligand1 (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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