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Background <p>To explore the effect of radiotherapy on anti-pd-1 anti-tumor activity in metastatic hepatocellular carcinoma.</p> Methods <p>Patients with metastatic HCC treated with intensity-modulated radiation therapy (IMRT) in combination with immunotherapy (<i>n</i> = 13) were retrospectively analyzed by comparing its efficacy with that of immunotherapy alone (<i>n</i> = 12) as well as untreated (<i>n</i> = 20) patients with metastatic hepatocellular carcinoma. Animal experiment used mouse hepatocellular carcinoma H22 cell metastatic tumor model and were also divided into a control group, a PD-1 antibody group, an SBRT group, and an SBRT combined with a PD-1 antibody group. SBRT treatment is 8&#xa0;Gy×3&#xa0;F. The growth curves of body weight, irradiated tumor (the primary tumor), and non-irradiated tumor (secondary tumor) were plotted for each group of tumor-bearing mice. For this study, we used flow cytometry to examine effector CD8 + T cells expression in both irradiated and non-irradiated tumors, the CD4 + T and CD4+/CD8 + T cells ratio in the spleen, and used enzyme-linked immunosorbent assays (ELISA) to analyze the concentrations of IFN-γ and IL-10 in serum. Tumors were additionally stained with immunohistochemistry Ki-67 and TdT-mediated dUTP nick end labeling (TUNEL). We used hematoxylin-eosin (HE) staining of liver, spleen, lungs, kidneys, and heart to assess the anti-tumor activity of each group of tumor-bearing mice and their tolerance to determine the safety of the approach.</p> Results <p>Clinical results: The median survival of IMRT + PD-1 group, PD-1 group, and control group were 17.5 months (95Confidence Interval (CI) 13.2–21.8), 12.5 months (95CI 9.0–16.0), and 5.2 months (95CI 5.5–12.9), respectively (<i>P</i> &lt; 0.001). SBRT combined with PD-1 antibody improved tumor control in both radiated and non-radiated tumors, resulting in a complete cure of the half of mice in animal studies. This was linked to an increased in CD8 + effector T cells infiltration triggered by radiotherapy. HE staining of mice in the SBRT combined with the PD-1 treatment group suggested no damage to the liver, spleen, lungs, kidneys, and heart.</p> Conclusions <p>This study showed that SBRT, while being well-tolerated, significantly increased anti-PD-1 antitumor activity by enhancing the tumor immune microenvironment in mice with metastatic hepatocellular carcinoma without significant toxic side effects.</p> Disclaimer <p>: This manuscript was previously submitted as a preprint only in Experimental Hematology &amp; Oncology and has no conflict of interest with this submission.</p>

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Stereotactic body radiation therapy (SBRT) increases anti-PD-1 antitumor activity by enhancing the tumor immune microenvironment in mice with metastatic hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月13日

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  • Ke Xu,
  • Tao Gu,
  • Ke Su,
  • Xin Liu,
  • Bingsheng He,
  • Jie He,
  • Hao Chi,
  • Xuancheng Zhou,
  • Hanlin Liu,
  • Rui Xiao,
  • Xue Tang,
  • Qinni Ye,
  • Xue Zhou,
  • Yingpeng Liu,
  • Jie Xiong,
  • Pan Wang,
  • Han Li,
  • Kun He,
  • Lu Guo,
  • Yunwei Han

摘要

Background

To explore the effect of radiotherapy on anti-pd-1 anti-tumor activity in metastatic hepatocellular carcinoma.

Methods

Patients with metastatic HCC treated with intensity-modulated radiation therapy (IMRT) in combination with immunotherapy (n = 13) were retrospectively analyzed by comparing its efficacy with that of immunotherapy alone (n = 12) as well as untreated (n = 20) patients with metastatic hepatocellular carcinoma. Animal experiment used mouse hepatocellular carcinoma H22 cell metastatic tumor model and were also divided into a control group, a PD-1 antibody group, an SBRT group, and an SBRT combined with a PD-1 antibody group. SBRT treatment is 8 Gy×3 F. The growth curves of body weight, irradiated tumor (the primary tumor), and non-irradiated tumor (secondary tumor) were plotted for each group of tumor-bearing mice. For this study, we used flow cytometry to examine effector CD8 + T cells expression in both irradiated and non-irradiated tumors, the CD4 + T and CD4+/CD8 + T cells ratio in the spleen, and used enzyme-linked immunosorbent assays (ELISA) to analyze the concentrations of IFN-γ and IL-10 in serum. Tumors were additionally stained with immunohistochemistry Ki-67 and TdT-mediated dUTP nick end labeling (TUNEL). We used hematoxylin-eosin (HE) staining of liver, spleen, lungs, kidneys, and heart to assess the anti-tumor activity of each group of tumor-bearing mice and their tolerance to determine the safety of the approach.

Results

Clinical results: The median survival of IMRT + PD-1 group, PD-1 group, and control group were 17.5 months (95Confidence Interval (CI) 13.2–21.8), 12.5 months (95CI 9.0–16.0), and 5.2 months (95CI 5.5–12.9), respectively (P < 0.001). SBRT combined with PD-1 antibody improved tumor control in both radiated and non-radiated tumors, resulting in a complete cure of the half of mice in animal studies. This was linked to an increased in CD8 + effector T cells infiltration triggered by radiotherapy. HE staining of mice in the SBRT combined with the PD-1 treatment group suggested no damage to the liver, spleen, lungs, kidneys, and heart.

Conclusions

This study showed that SBRT, while being well-tolerated, significantly increased anti-PD-1 antitumor activity by enhancing the tumor immune microenvironment in mice with metastatic hepatocellular carcinoma without significant toxic side effects.

Disclaimer

: This manuscript was previously submitted as a preprint only in Experimental Hematology & Oncology and has no conflict of interest with this submission.