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Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

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Fig. 1: H101 inhibits B16F10 tumor growth in vivo.
Fig. 2: H101 promotes the infiltration of immune cells to inhibit melanoma.
Fig. 3: H101 has low cytotoxicity on B16F10 cells, but can induce HUVEC death in vitro.
Fig. 4: H101 induces the pyroptosis of endothelial cells via caspase-1/GSDMD.
Fig. 5: Pyroptosis inhibitor Z-VAD-FMK reverses the tumor suppression effect of H101.
Fig. 6: Combination therapy of H101 and PD-L1 antibody enhances tumor suppression.

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Acknowledgements

This work was supported by National Key Research and Development Program of China (2023YFA0913700), National Natural Science Foundation of China (82073858, 82173821, 82273934, and 82373875), Natural Science Foundation of Shanghai (21ZR1432700), the open project of Anhui Province Key Laboratory of Translational Cancer Research (KFKT202302), Anhui Province Scientific Research Compilation Plan Project (2022AH040214), Anhui Province Translational Special Project for Clinical Medical Research (202204295107020038), Shanghai Society of Biotechnology (SSBT), Key Research and Development Projects in Anhui Province for A (202104j07020021).

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  1. These authors contributed equally: Zhi-ming Wang, Meng-kai Li, Qing-ling Yang

Authors and Affiliations

  1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Zhi-ming Wang, Meng-kai Li, Shi-xin Duan, Xin-yi Lou, Xin-yi Yang, Ying Liu, Yu-wen Zhong, Lei Sun & Feng Qian

  2. Anhui Province Key Laboratory of Cancer Translational Medicine, Bengbu Medical University, Bengbu, 233030, China

    Qing-ling Yang & Yu Qiao

  3. Department of Medical Oncology, Anhui Province Key Laboratory of Translational Cancer Research, First Affiliated Hospital of Bengbu Medical College, Bengbu Medical University, Bengbu, 233004, China

    Zi-shu Wang

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Contributions

FQ, LS, and ZSW conceived the study. ZSW, MKL, and QLY performed and interpreted experimental data. LS, FQ, ZMW, MKL, and QLY wrote the paper. SXD, XYL, XYY, YL, YWZ, and YQ prepared figures. All authors read and approved the final manuscript.

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Correspondence to Zi-shu Wang, Lei Sun or Feng Qian.

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Wang, Zm., Li, Mk., Yang, Ql. et al. Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01349-x

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