Abstract
The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor. OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines.
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Data availability
The gene sequences of WSN influenza virus strain used in this study have been deposited in GenBank under accession numbers CY034138.1, CY034139.1, CY034135.1, CY034134.1, X17336.1, HE802059.1, L25818.1 and CY034136.1. Three-dimensional structures of HA have been deposited in the Protein Data Bank (PDB) with PDB ID 1RVT. All requests for raw and analyzed data and materials are promptly reviewed by our institution to verify whether the request is subject to any intellectual property or confidentiality obligations. Any data and materials that can be shared will be released via a material transfer agreement. All other data that support the findings of this study will be provided by the corresponding author upon reasonable request when possible. All data generated or analyzed during this study are included in the published article and its Supplementary Information files. Source data are provided with this paper.
Change history
13 July 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41587-023-01884-8
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Acknowledgements
We acknowledge the Department of Laboratory Animal Science at Peking University Health Science Center for assistance with animal experiments. We acknowledge Sangon Biotech Ltd., GeneWiz lnc. and Top Peptide Inc. for gene sequencing, plasmid construction and peptide synthesis. We thank B. Xu and relevant staff from the State Key Laboratory of Natural and Biomimetic Drugs for support of technical and experimental platforms. We thank C. Gong (Sichuan University) for gifting the B16-F10-OVA cell line and Y. Wang (Peking University) for gifting the 4T1-luci cell line. We thank Z. Jiang (Peking University) for support with flow cytometry technology; L. Zhang (Peking University) for support with transmission electron microscopy; and X. Yan (Xiamen University) for support with nanoflow work. This work was supported by the National Natural Science Foundation of China (grant no. 82130100 to D.Z., grant no. 81821004 to D.Z., grant no. 2017ZX09309009 to D.Z., grant no. 91753202 D.Z. and grant no. 82204258 to D.J.), the Ningbo Key Science and Technology Development Program (grant no. 2022Z136 to D.Z), the Ningbo Yongjiang Talent Introduction Program (grant no. 2022A-157-G to D.J.) and the China Postdoctoral Science Foundation (grant no. 2019M650394 to D.J. and grant no. BX20180017 to D.J.).
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D.J. and Y.Z. designed and performed most experiments and analyzed the data. J.S. and B.Z. contributed to experimental designs and assisted with the experiments on immune cell identification in vitro and in vivo. W.M. and B.C. performed experiments with influenza virus. X.W., Y.L. and Z.C. assisted with animal efficacy evaluation. H.X. performed transgenic cell line construction. S.X., Q.W. and C.Z. contributed to the collection and assembly of data and polished the language. L.Z. provided comments. D.J. wrote the first draft of the paper. D.Z. and D.J. supervised all the experiments and revised the final manuscript. All of the authors reviewed the manuscript.
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D.Z., D.J. and Y.Z. are inventors on relevant patent applications held by the Ningbo Institute of Marine Medicine, Peking University. The remaining authors declare no competing financial interests.
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Ji, D., Zhang, Y., Sun, J. et al. An engineered influenza virus to deliver antigens for lung cancer vaccination. Nat Biotechnol 42, 518–528 (2024). https://doi.org/10.1038/s41587-023-01796-7
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DOI: https://doi.org/10.1038/s41587-023-01796-7
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