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Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC

Cancer Gene Therapy volume 32, pages 71–82 (2025) Cite this article

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Abstract

Previous studies have found that oncolytic virus (OVs) can improve the efficacy of TIL adoptive therapy in oral cancer, colon cancer, and pancreatic cancer. However, the curative effect in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the therapeutic effect and mechanism of OVs encoding 4-1BBL and IL15 (OV-4-1BBL/IL15) combined with TIL adoptive therapy on HCC. In this study, the role and immunological mechanism of armed OVs combined with TILs were evaluated by flow cytometry and ELISA in patient-derived xenograft and syngeneic mouse tumor models. Co-culturing with TILs can up-regulate the expression of antigen-presenting cell (APC) markers on the surface of OV-infected primary HCC cells, and promote the specific activation ability and tumor-killing ability of TILs. OV-4-1BBL/IL15 combined with TIL adoptive therapy could induce tumor volume reduction and anti-tumor immune memory in patient-derived xenograft and syngeneic mouse tumor models. Furthermore, OV combined with TIL adoptive therapy can endow tumor cells with aAPC characteristics, activate T cells at the same time, and reprogram tumor macrophages into anti-tumor phenotype. OV-4-1BBL/IL15 can stimulate the anti-tumor potential of TIL therapy in HCC, and possess broad clinical application prospects.

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Fig. 1: Generation of engineered OVs encoding trimerized 4-1BBL and/or IL15.
The alternative text for this image may have been generated using AI.
Fig. 2: OV-4-1BBL/IL15 transformed tumor cells into aAPCs to activate tumor-specific T cells.
The alternative text for this image may have been generated using AI.
Fig. 3: Anti-tumor efficacy of the combination therapy with OV-4-1BBL/IL15 and TILs in patient-derived xenograft tumor models.
The alternative text for this image may have been generated using AI.
Fig. 4: Combination therapy with OV-m4-1BBL/IL15 and TILs led to marked tumor regression in immunocompetent murine tumor models.
The alternative text for this image may have been generated using AI.
Fig. 5: Analysis of tumor cells and tumor-infiltrating immune cells after the tumor-bearing mice were treated with the OV and TILs.
The alternative text for this image may have been generated using AI.
Fig. 6: The regulatory effect of OV-infected HCC cells on the phenotype of TILs.
The alternative text for this image may have been generated using AI.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Funding

This work was supported by the National Science and Technology Major Project (No.2023ZD0508702), Natural Science Foundation of Tianjin (23JCYBJC00950), Tianjin Health Science and Technology Project key discipline special (TJWJ2022XK034), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-059B), Research project in key areas of TCM in 2024 (2024022), Tianjin Municipal Education Commission Scientific Research Planning Project (2023KJ015).

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Author notes

  1. These authors contributed equally: Kai Ye, Yongfeng Yan.

Authors and Affiliations

  1. Clinical School of the Second People’s Hospital, Tianjin Medical University, Tianjin, China

    Kai Ye, Rui Su, Qinghai Dai, Kunyan Qiao, Yu Cao, Jian Xu, Lihua Yan, Zhixiao Huo, Wei Liu, Yue Hu, Liang Xu & Yuqiang Mi

  2. Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, Tianjin, China

    Kai Ye, Rui Su, Qinghai Dai, Kunyan Qiao, Yu Cao, Jian Xu, Lihua Yan, Zhixiao Huo, Wei Liu, Yue Hu, Liang Xu & Yuqiang Mi

  3. Tianjin Integrated Traditional Chinese and Western Medicine Institute of Infectious Diseases, Tianjin, China

    Kai Ye, Rui Su, Qinghai Dai, Kunyan Qiao, Yu Cao, Jian Xu, Lihua Yan, Zhixiao Huo, Wei Liu, Yue Hu, Liang Xu & Yuqiang Mi

  4. Department of Laboratory, Tianjin Beichen Hospital, Tianjin, China

    Yongfeng Yan

  5. School of Precision Instruments and Opto-Electronics Engineering, Tianjin University, Tianjin, China

    Rui Su

  6. Department of Clinical Laboratory, The Third Central Hospital of Tianjin, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China

    Yu Zhu

  7. Department of hepatology & oncology, Tianjin Second People’s Hospital, Tianjin, China

    Liang Xu

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Contributions

KY and YY conceived the study. YZ, LX, and YM supervised the project. KY and RS designed all experiments. KY, YY, RS, QD, KQ, YC, JX, LY, ZH, WL and YH performed the experiments. KY, KQ, and YC generated the recombinant viruses. KY, YY, and JX conducted the in vivo experiments. LY and ZH assisted with the viral construction, production, and characterization. KY, QD, and WL analyzed the FACS data. KY, YY, and RS discussed the results and wrote the manuscript.

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Correspondence to Rui Su, Yu Zhu, Liang Xu or Yuqiang Mi.

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Ye, K., Yan, Y., Su, R. et al. Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC. Cancer Gene Ther 32, 71–82 (2025). https://doi.org/10.1038/s41417-024-00853-w

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