Abstract
Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.
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Data availability
The scRNA-seq data are available in the NCBI Gene Expression Omnibus (GEO) under accession no. GSE164487. The bulk messenger RNA-seq data are available in the GEO under accession no. GSE179783. Source data are provided with this paper. The authors declare that other data supporting the findings of this study are available within this article and its supplementary information; all additional data are available from the corresponding author upon reasonable request.
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Acknowledgements
This research was supported by grants from the National Cancer Institute (no. 1R01CA264102-01 to D.Z.) and Wake Forest Comprehensive Cancer Center no. P30 CA01219740. W.Z. is supported by the Hanes and Willis Family Professorship and a Fellowship from the National Foundation for Cancer Research. A.A.H is supported by funding from the Department of Veteran’s Affairs (no. 2I01BX002559-07) and from the National Institutes of Health (no. 1R01CA244212-01A1). We thank W. Cui, L. Craddock and J. Chou of the Cancer Genomics shared Resource for conducting the scRNA-seq. We thank L. McWilliams, Biorepository Coordinator, for handling and delivering the patient samples. We also thank R. Singh, Cancer Biology, X. Yuan and C. Arledge, Biomedical Engineering, for technical and collegial support. We acknowledge the use of Servier Medical Art (https://smart.servier.com) templates, which are licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/), to compile Fig. 6a.
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Y. Liu and D.Z. conceptualized the study. Y. Liu, L.W., W.N.C., D.Z., Q.S. and Y. Lu were responsible for the methodology. Q.S., G.A.H., W.Z., L.D.M., W.N.C., L.W. and Y. Liu were responsible for the software. Y. Liu, L.W., W.N.C. and Q.S. carried out the formal analysis. Y. Liu, L.W., Q.S., M.A., W.J.P. and D.Z. carried out the investigation. M.A., G.L.K., S.S., G.A.H., L.D.M., M.A., K.W.T. and C.R.B. were responsible for resources. Y. Liu, G.A.H. and L.D.M. were responsible for data curation. Y. Liu, L.W. and D.Z. wrote the original draft. Y. Liu, M.A., Q.S., W.N.C., Y. Lu, C.R.B., W.Z., A.A.H., W.J.P. and D.Z. reviewed and edited the manuscript. C.R.B., W.J.P. and D.Z. supervised the study. Y. Liu, L.W., Q.S., W.N.C. and D.Z. were responsible for data visualization.
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Peer review information Nature Nanotechnology thanks Jinming Gao, Daniel Sterman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Information
Supplementary Figs .1–29, Tables 1–3 and Methods.
Supplementary Table 1
Significantly enriched terms in the GO and KEGG analysis based on the gradually up and down-regulated genes in the M2 to M1 repolarization. Related Fig. 2.
Supplementary Table 2
Full list of genes expression, GO, and KEGG pathways enrichment analysis in MPE in pleural fluids of LLC MPE mice after LNP-CDN treatment. Related to Supplementary Fig. 10.
Supplementary Table 3
Full list of genes expression, GO, and KEGG pathways enrichment analysis in pleural tumour in pleural fluids of LLC MPE mice after LNP-CDN treatment. Related to Supplementary Fig. 11.
Supplementary Table 4
Full differential expression gene list between subclusters of CD8 T cells. Related to Fig. 3.
Supplementary Data
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Liu, Y., Wang, L., Song, Q. et al. Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion. Nat. Nanotechnol. 17, 206–216 (2022). https://doi.org/10.1038/s41565-021-01032-w
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DOI: https://doi.org/10.1038/s41565-021-01032-w
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