Abstract
Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.
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Data availability
All the data supporting the findings of this study are available within the article and its Supplementary Information and from the corresponding authors upon reasonable request. Source data are provided with this paper. The GO analysis was based on the Panther database (https://www.pantherdb.org/).
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Acknowledgements
We thank the National Key R&D Program of China (2021YFA0909900), the National Natural Science Foundation of China (52173142 and 52233013) and Zhejiang University for the grants from the Startup Package.
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Z.G., H.L. and P.Z. initiated the project concept. J. Shi, W. Wu, D.C., Z.L., T.S., Y.W., Y.Y., Q.W., F.L., R.Z., C.Z. and X.S. performed the experiments and collected the data. Z.M., Y.D. and W. Wang provided support for the PDX model. G.D., J. Sun, X.L., W.F. and D.C. helped with data analysis. J. Shi, W. Wu, H.L. and Z.G. wrote the paper.
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Related patents have been applied for by Z.G., H.L., J. Shi and W. Wu (patent applicant: Zhejiang University; name of inventors: Zhen Gu, Hongjun Li, Jiaqi Shi, Wei Wu; application number: 2022113666477; status of application: substantive examination; specific aspect of paper covered in patent application: preparation of CAR T cell-loaded lyophilizing lymph nodes and its anti-tumour application). Z.G. is the cofounder of Zenomics Inc., ZCapsule Inc. and µZen Inc. The other authors declare no competing interests.
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Shi, J., Wu, W., Chen, D. et al. Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells. Nat. Mater. (2024). https://doi.org/10.1038/s41563-024-01825-z
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DOI: https://doi.org/10.1038/s41563-024-01825-z
