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SOCS3 inhibiting JAK-STAT pathway enhances oncolytic adenovirus efficacy by potentiating viral replication and T-cell activation

Cancer Gene Therapy volume 31, pages 397–409 (2024)Cite this article

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Abstract

Oncolytic viruses (OVs) are emerging as a potentially useful treatment for malignancies due to the capabilities of direct oncolysis and immune induction. Improving the replication of OVs is an effective approach to enhance the oncolytic effects. Here, we observed that cancer cells with deficiencies in JAK-STAT pathway showed greater sensitivity to oncolytic adenovirus (oAd), and JAK inhibitor could enhance the replication of oAd. Therefore, we constructed a novel oAd expressing SOCS3, a major negative regulator of JAK-STAT pathway, and confirmed that oAd-SOCS3 exhibited a more significant antitumor effect than oAd-Ctrl both in vitro and in vivo. Mechanistically, SOCS3 inhibited the activation of JAK-STAT pathway, resulting in stronger tumor selective replication of oAd and downregulated expression of PD-L1 on cancer cells as well. Both benefits could collectively awaken antitumor immunity. This study highlights the importance of JAK-STAT pathway in viral replication and confirms the treatment of oAd-SOCS3 in potential clinical applications.

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Fig. 1: Loss of function in JAK-STAT pathway increased sensitivity to oAd.
Fig. 2: Construction and characteristics of oAd-SOCS3.
Fig. 3: Viral replication of oAd-SOCS3 in vitro.
Fig. 4: oAd-SOCS3 improved oncolytic virotherapy of cancer in a breast cancer xenograft model.
Fig. 5: oAd-SOCS3 mediated oncolysis increased anti-tumor immune response.
Fig. 6: The replication-deficient Ad-SOCS3 demonstrated a limited ability to control tumor growth.

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Data availability

The data and materials used in this study are available from the corresponding authors upon reasonable request.

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Funding

Funding

The National Key Technology Research and Development Program of China (2022YFC2704200 and 2022YFC2704205); National Science and Technology Major Sub-Project (2018ZX10301402-002); Beijing Xisike Clinical Oncology Research Foundation (Y-2019AZZD-0359); National Natural Science Foundation of China (81772787, 82072889, 82103456); Technical Innovation Special Project of Hubei Province (2018ACA138); China Postdoctoral Science Foundation (2023M731198).

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Authors and Affiliations

  1. Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Danmei Yan, Guannan Li, Yuan Yuan, Huayi Li, Heng Cao, Yilin Dai, Ying Li, Zeyu Zhang, Fei Li, Yong Fang & Qinglei Gao

  2. National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Danmei Yan, Guannan Li, Yuan Yuan, Huayi Li, Heng Cao, Yilin Dai, Ying Li, Zeyu Zhang, Fei Li, Yong Fang & Qinglei Gao

  3. Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China

    Yuan Yuan

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Contributions

QLG and YF conceived and designed the project, supervised the study and prepared the manuscript. DMY performed experimental work, interpreted the data, draft the work and prepared the manuscript. GNL performed experimental work and interpreted the data. YY, HC, YLD, YL, and ZYZ performed experimental work. HYL and FL contributed to language editing. All authors read and approved the final manuscript.

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Correspondence to Yong Fang or Qinglei Gao.

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All animal experiments were approved by the Committee on Ethics of Animal Experiments of Tongji Hospital (TJH-202112004).

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Yan, D., Li, G., Yuan, Y. et al. SOCS3 inhibiting JAK-STAT pathway enhances oncolytic adenovirus efficacy by potentiating viral replication and T-cell activation. Cancer Gene Ther 31, 397–409 (2024). https://doi.org/10.1038/s41417-023-00710-2

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