Kim Kyoung-Jin, Kim Ji-Hye, Lee Seo Jin, Lee Eun-Jung, Shin Eui-Cheol, Seong Jinsil
Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Techonology, Daejeon, Republic of Korea.
Oncotarget. 2017 Jun 20;8(25):41242-41255. doi: 10.18632/oncotarget.17168.
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.
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.
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.
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.
尽管免疫疗法已成为难治性癌症颇具吸引力的治疗方法，但其在肝细胞癌（HCC）中的疗效有限，这表明需要一种能够增强或补充治疗效果的联合策略。我们研究了免疫检查点阻断（ICB）与放疗联合是否能增强小鼠肝癌模型的抗肿瘤效果。
使用小鼠肝癌细胞系HCa-1，通过实时PCR、流式细胞术和蛋白质印迹法测定放疗对程序性死亡配体1（PD-L1）表达的影响。检测参与PD-L1表达改变的信号通路。评估抗PD-L1与放疗联合治疗的肿瘤生长和生存率。使用流式细胞术和组织学研究评估肿瘤中的免疫参数。
放疗通过IFN-γ/STAT3信号通路上调肿瘤细胞中PD-L1的表达，这可促进抗PD-L1的治疗作用。与单独使用抗PD-L1或单独放疗组相比，抗PD-L1与放疗联合显著抑制肿瘤生长（P<0.01）。与单独使用抗PD-L1或单独放疗组相比，联合组的生存率显著提高（7周生存率；分别为90%对0%或30%，P<0.001）。潜在机制包括增加细胞凋亡、减少肿瘤细胞增殖以及恢复CD8+T细胞功能。
抗PD-L1与放疗联合显著改善了肿瘤生长延迟和生存率方面的抗肿瘤效果，支持了肝癌免疫放疗的一种新型联合策略。
