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Combination therapy with dendritic cell loaded-exosomes supplemented with PD-1 inhibition at different time points have superior antitumor effect in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC), a prevalent cause of cancer-related deaths, is insensitive to traditional treatments. At different time intervals, the combined antitumor effects of DC-TEX and the programmed death protein 1 (PD-1) antibody (Ab) have not been investigated. In this study, HCC models were established and treated at different time intervals with DC-TEX alone or in combination with PD-1 Ab. In addition, we developed an orthotopic HCC model in BALB/c nude mice and restored T cells. Results demonstrated that the PD-1 + CD8 + T-cell population also increased significantly after DC-TEX treatment, in addition to the increased number of CD8 + T cells. The number of CD8 + T cells increased 72 h after DC-TEX administration. Similar observations were made for PD-1 + CD8 + T cells. Subsequently, PD-1 Ab was administered in combination with DC-TEX at different time points (0, 24, 72, 96, 120, or 168 h). Surprisingly, the combination treatment demonstrated a strong antitumor effect, which was very prominent when PD-1 Ab was administered at 72 h. PD-1 Ab significantly reversed the proliferative ability of PD-1 + CD8 + T cells at 72 h in vitro. The combined antitumor effects of PD-1 Ab and DC-TEX occurred mainly by stimulating CD8 + T cell proliferation and inhibiting T cell exhaustion. In conclusion, our results indicate that the combination of DC-TEX and PD-1 Ab significantly inhibits tumor growth in a murine HCC model and that the timing of PD-1 Ab administration impacts the antitumor effect.

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Acknowledgements

This work was supported by the Peking Union Medical College Innovation Research Team Fund, the Union Young Fund of Peking Union Medical College (3332016105) and the Sci-tech Development Project of Shandong Medicine and Health (2016WS0552) and the Natural Science Foundation of Shandong (ZR2017PH024) and the National Natural Science Foundation of China (81702821).

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Authors and Affiliations

  1. Department of Gastrointestinal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, #440 Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China

    Chunxiao Chang, Wenyu Zhang & Shengbin Shi

  2. Department of Infection Management, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China

    Yanqing Pei

  3. Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin Key Laboratory of Biomaterial Research, Tianjin, 300192, China

    Chuangnian Zhang, Yibo Qin & Shengbin Shi

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  1. Chunxiao Chang
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  2. Yanqing Pei
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  3. Chuangnian Zhang
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  4. Wenyu Zhang
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Contributions

CC and YP performed the experiments, analyzed the data and prepared the manuscript. CZ and WZ aided the data analysis and manuscript preparation. YQ contributed data analysis. SS designed and supervised the study, analyzed the data, prepared and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shengbin Shi.

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Chang, C., Pei, Y., Zhang, C. et al. Combination therapy with dendritic cell loaded-exosomes supplemented with PD-1 inhibition at different time points have superior antitumor effect in hepatocellular carcinoma. Cancer Immunol Immunother 72, 3727–3738 (2023). https://doi.org/10.1007/s00262-023-03525-0

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