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Oncolytic Newcastle disease virus expressing the co-stimulator OX40L as immunopotentiator for colorectal cancer therapy

Gene Therapy volume 30, pages 64–74 (2023)Cite this article

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Abstract

NDV as an attractive candidate for oncolytic immunotherapy selectively lyses tumor cells but shows limited anti-tumor immunity. Immune co-stimulator OX40 ligand (OX40L) boosts anti-tumor immunity response by delivering a potent costimulatory signal to CD4+ and CD8+ T cells. To improve the anti-tumor immunity of NDV, the recombinant NDV expressing the murine OX40L (rNDV-mOX40L) was engineered. The viral growth kinetics was examined in CT26 cell lines. The ability of rNDV-mOX40L to express mOX40L was detected in the infected tumor cells and tumor tissues. The anti-tumor activity of rNDV-mOX40L was studied in the CT26 animal model. Tumor-specific CD4+, CD8+ and OX40+ T cells were examined by immunohistochemistry staining. The virus growth curve showed that the insertion of the mOX40L gene did not affect the growth kinetics of NDV. rNDV-mOX40L expresses mOX40L and effectively inhibits the growth of CT26 colorectal cancer in vivo. The tumor inhibition rate of the rNDV-mOX40L-treated group was increased by 15.8% compared to that of  NDV-treated group in the CT26 model. Furthermore, immunohistochemistry staining of tumor tissues removed from the CT26 model revealed that intense infiltration of tumor-specific CD4+, CD8+ T cells, especially OX40+ T cells were found in the rNDV-mOX40L-treated group. FACS showed that rNDV-mOX40L significantly enhanced the number of CD4+ and CD8+ T cells in spleen. Moreover, compared to the NDV-treated group, the level of mouse IFN-γ protein in the tumor site increased significantly in the rNDV-mOX40L-treated group. Taken together, rNDV-mOX40L exhibited superior anti-tumor immunity by stimulating tumor-specific T cells and may be a promising agent for cancer immunotherapy.

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Fig. 1: Construction and growth curve of rNDV-mOX40L.
Fig. 2: In vitro cytotoxicity evaluation of rNDV-mOX40L.
Fig. 3: rNDV-mOX40L show enhanced oncolytic effect in CT26 model.
Fig. 4: Expression of mOX40L protein in vivo.
Fig. 5: H&E and immunohistochemistry staining of tumor tissues in CT26 model.
Fig. 6: Enhancement of splenic immune response induced by rNDV-mOX40L.
Fig. 7: The rNDV-mOX40L promotes IFN-γ production in tumor tissues.

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Acknowledgements

This work was financially supported by the National Key R&D Program of China (2017YFD0501102).

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  1. Deshan Li

    Present address: College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China

Authors and Affiliations

  1. College of Life Science, Northeast Agricultural University, Harbin, China

    Limin Tian, Yukai Cao, Kai Kang, Han Su, Guiping Ren & Deshan Li

  2. Jiangsu Kanion Pharmaceutical CO. LTD, State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, Jiangsu, China

    Tianyan Liu, Shan Jiang, Zhenzhong Wang & Wei Xiao

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Contributions

LT: conceptualization, methodology, validation, formal analysis, investigation, writing-original draft, visualization. DL: conceptualization, methodology, validation, supervision, resources, data curation. WX: methodology, project administration, funding acquisition, data curation. TL: validation, methodology, investigation. YC: validation, investigation. SJ: validation, software. HS: validation, investigation. KK: validation, investigation. ZW: project administration, funding acquisition. GR: methodology, resources.

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Correspondence to Wei Xiao or Deshan Li.

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Tian, L., Liu, T., Jiang, S. et al. Oncolytic Newcastle disease virus expressing the co-stimulator OX40L as immunopotentiator for colorectal cancer therapy. Gene Ther 30, 64–74 (2023). https://doi.org/10.1038/s41434-021-00256-8

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