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Oncolytic adenovirus encoding LIGHT (TNFSF14) inhibits tumor growth via activating anti-tumor immune responses in 4T1 mouse mammary tumor model in immune competent syngeneic mice

Cancer Gene Therapy volume 27, pages 923–933 (2020)Cite this article

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Abstract

LIGHT, also known as tumor-necrosis factor (TNF) superfamily member 14 (TNFSF14), is predominantly expressed on activated immune cells and some tumor cells. LIGHT is a pivotal regulator both for recruiting and activating immune cells in the tumor lesions. In this study, we armed human telomerase reverse transcriptase (TERT) promoter controlled oncolytic adenovirus with LIGHT to generate rAd.Light. rAd.Light effectively transduced both human and mouse breast tumor cell lines in vitro, and expressed LIGHT protein on the surface of tumor cells. Both rAd.Null, and rAd.Light could replicate in human breast cancer cells, and produced cytotoxicity to human and mouse mammary tumor cells. rAd.Light induced apoptosis resulting in tumor cell death. Using a subcutaneous model of 4T1 cells in BALB/c mice, rAd.Light was delivered intratumorally to evaluate the anti-tumor responses. Both rAd.Light and rAd.Null significantly inhibited the tumor growth, but rAd.Light produced much stronger anti-tumor effects. Histopathological analysis showed the infiltration of T lymphocytes in the tumor tissues. rAd.Light also induced stronger cellular apoptosis than rAd.Null in the tumors. Interestingly, on day 15, compared to rAd.Null, there was a significant reduction of Tregs following rAd.Light treatment. rAd.Light significantly increased Th1 cytokine interleukin (IL)-2 expression, and reduced Th2 cytokines expression, such as transforming growth factor β (TGF-β) and IL-10 in the tumors. These results suggest rAd.Light induced activation of anti-tumor immune responses. In conclusion, rAd.Light produced anti-tumor effect in a subcutaneous model of breast cancer via inducing tumor apoptosis and evoking strong anti-tumor immune responses. Therefore, rAd.Light has great promise to be developed as an effective therapeutic approach for the treatment of breast cancer.

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Fig. 1: Construction of oncolytic adenovirus rAd.Light, viral replication, viral-induced cytotoxicity, and viral-mediated LIGHT expression in breast cancer cell lines.
Fig. 2: Oncolytic adenovirus expressing LIGHT, rAd.Light produced anti-tumor responses in subcutaneous model of mouse breast cancer.
Fig. 3: rAd.Light promotes tumor infiltration of CD3+ T cells, produces LIGHT protein, promotes infiltration of T lymphocytes and regulates Th1/Th2 cytokines balance in tumor microenvironment.
Fig. 4: Intratumoral delivery of rAd.Light up-regulates CD8+ T lymphocytes, promoting CD4+ T memory cells and reducing regulatory T cells in peripheral blood.

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Acknowledgements

This work was supported by Nova Program of Beijing (Z171100001117118). Funding at NorthShore was provided by a Clinical and Translational Science Award (PS).

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  1. These authors contributed equally: Shiyun Dai, Yun Lv

Authors and Affiliations

  1. Anhui Medical University, Hefei, 230032, Anhui, PR China

    Shiyun Dai, Yun Lv & Hua Wang

  2. Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China

    Shiyun Dai, Yun Lv, Yuefeng Yang, Chao Liu, Xiwen Dong, Huan Zhang & Hua Wang

  3. Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL, USA

    Weidong Xu, Yuefeng Yang & Prem Seth

  4. Department of Experimental Medical Science & Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, 315000, Zhejiang, PR China

    Yuefeng Yang

  5. Binzhou Medical University, Yantai, 264003, Shandong, PR China

    Chao Liu

  6. The Fifth Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, PR China

    Huan Zhang

  7. Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA

    Bellur S. Prabhakar & Ajay V. Maker

  8. Department of Surgery, Division of Surgical Oncology, University of Illinois, Chicago, IL, USA

    Ajay V. Maker

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Contributions

HW and PS, conceived and designed the work; SD, YL, WX, CL, XD, and HZ, performed experiments and collected data; YY, BP and AM, analyze and interpret the results; HW and PS wrote the manuscript; PS, BP, and AM revised the manuscript and modified the language.

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Correspondence to Prem Seth or Hua Wang.

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Dai, S., Lv, Y., Xu, W. et al. Oncolytic adenovirus encoding LIGHT (TNFSF14) inhibits tumor growth via activating anti-tumor immune responses in 4T1 mouse mammary tumor model in immune competent syngeneic mice. Cancer Gene Ther 27, 923–933 (2020). https://doi.org/10.1038/s41417-020-0173-z

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