Abstract
Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1β secretion. The elevated interleukin-1β increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. There are no data from third-party or publicly available datasets. The accession number for the raw data files for the transcriptome and ATAC sequencing reported in this paper is NCBI PRJNA861796. Other source data that support the findings of this study are available from the corresponding authors upon reasonable request. Source data for Figs. 1–5 are available in separate source data files for Figs. 1b,e–g, 2a–c,e–g,i,k, 3a–b,e,d, g-i, 4b–c,e,g–j and 5b,e,g–j, respectively. Source data for Extended Data Fig. 1 are available in separate source data files for Extended Data Fig. 1a–b,d–f. Source data for PDFs 1–3 are available in separate source data files for Figs. 1a, 4c,d and 5c,d. Supplementary XLSs 1–43 are available in separate supplementary files for Supplementary Figs. 1b, 3b,c, 4b,c, 6b,d–f, 7b–d, 8c–g, 11a–c, 16b–e, 17b,c, 18b, 21, 23b,c, 24, 25a,b, 26b–e, 27, 28b,c, 29a–d and 30a,b, respectively. Supplementary Fig. 1 and Supplementary PDFs 1–5 are available in separate supplementary files for Supplementary Figs. 18a, 19, 20, 28a,c and 29d, respectively. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the National Key R&D Program of China (2021YFA0909900 and 2022YFB3808100, X.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB36000000, G.N.), the CAS Project for Young Scientists in Basic Research (YSBR-010, X.Z.), the Beijing Natural Science Foundation (Z200020, X.Z.) and the National Natural Science Foundation of China (32222045 and 32171384, X.Z.). In addition, we would like to thank Wenjuan Zhang for her help on cryo-EM sampling and imaging at the Cryo-electron Microscopy Platform, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences (IGDB).
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Contributions
G.L., N.M., K.C., X.Z. and G.N. designed the research. G.L., N.M., K.C., Q.F., X.M., Y.Y., Y.L., T.Z., X.G., J.L., L.Z. and X.W. performed the research. Z.R. and Y.-X.F. provided professional support for animal studies. All authors analysed and interpreted the data. G.L., X.Z. and G.N. wrote the paper.
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Extended data
Extended Data Fig. 1 OMVs improved the antitumour efficacy of subsequent tumour vaccinations.
(a) The antitumour efficacy enhancement of subsequent tumour vaccinations in pulmonary metastatic B16-OVA tumour model mice (n = 6 biologically independent mice per group). (b) Antitumour efficacy enhancement of subsequent tumour vaccinations in subcutaneous MC38 tumour models mice (n = 8 biologically independent mice per group). (c–f) The antitumour efficacy enhancement of subsequent tumour vaccinations in long-term immune memory models. (C) Schematic illustration of the experiment schedule and group information. (D) Proportions of effector memory T cells (Tem, CD3+CD8+CD44+CD62L−) and central memory T cells (Tcm, CD3+CD8+CD44+CD62L+) in splenocytes on day 60, as determined by flow cytometry (n = 6 biologically independent mice per group). (E) Growth curves of the subcutaneous tumours in each mouse challenged by subcutaneous inoculation with MC38 cells (n = 10). (F) Survival curves of the mice from day 90 (n = 10). The data were processed on GraphPad Prism software (v8.3.0.538) and are presented as the mean ± SD. The P values were determined using one-way ANOVA with a Tukey post hoc test. Survival significance was analysed by the two-sided log-rank test. ns, no significance; *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Supplementary information
Supplementary Information
Table of contents, Supplementary Discussion, Figs. 1–35 and Tables 1–3.
Supplementary Table 1
Raw dataset for Supplementary Fig. 1b.
Supplementary Table 2
Raw dataset for Supplementary Fig. 3b.
Supplementary Table 3
Raw dataset for Supplementary Fig. 3c.
Supplementary Table 4
Raw dataset for Supplementary Fig. 4b.
Supplementary Table 5
Raw dataset for Supplementary Fig. 4c.
Supplementary Table 6
Raw dataset for Supplementary Fig. 6b.
Supplementary Table 7
Raw dataset for Supplementary Fig. 6d.
Supplementary Table 8
Raw dataset for Supplementary Fig. 6e.
Supplementary Table 9
Raw dataset for Supplementary Fig. 6f.
Supplementary Table 10
Raw dataset for Supplementary Fig. 7b.
Supplementary Table 11
Raw dataset for Supplementary Fig. 7c.
Supplementary Table 12
Raw dataset for Supplementary Fig. 7d.
Supplementary Table 13
Raw dataset for Supplementary Fig. 8c.
Supplementary Table 14
Raw dataset for Supplementary Fig. 8d.
Supplementary Table 15
Raw dataset for Supplementary Fig. 8e.
Supplementary Table 16
Raw dataset for Supplementary Fig. 8f.
Supplementary Table 17
Raw dataset for Supplementary Fig. 8g.
Supplementary Table 18
Raw dataset for Supplementary Fig. 11a.
Supplementary Table 19
Raw dataset for Supplementary Fig. 11b.
Supplementary Table 20
Raw dataset for Supplementary Fig. 11c.
Supplementary Table 21
Raw dataset for Supplementary Fig. 16b.
Supplementary Table 22
Raw dataset for Supplementary Fig. 16c.
Supplementary Table 23
Raw dataset for Supplementary Fig. 16d.
Supplementary Table 24
Raw dataset for Supplementary Fig. 16e.
Supplementary Table 25
Raw dataset for Supplementary Fig. 17b.
Supplementary Table 26
Raw dataset for Supplementary Fig. 17c.
Supplementary Table 27
Raw dataset for Supplementary Fig. 18b.
Supplementary Table 28
Raw dataset for Supplementary Fig. 21.
Supplementary Table 29
Raw dataset for Supplementary Fig. 23b.
Supplementary Table 30
Raw dataset for Supplementary Fig. 23c.
Supplementary Table 31
Raw dataset for Supplementary Fig. 24.
Supplementary Table 32
Raw dataset for Supplementary Fig. 25a.
Supplementary Table 33
Raw dataset for Supplementary Fig. 25b.
Supplementary Table 34
Raw dataset for Supplementary Fig. 26b.
Supplementary Table 35
Raw dataset for Supplementary Fig. 26c.
Supplementary Table 36
Raw dataset for Supplementary Fig. 26d.
Supplementary Table 37
Raw dataset for Supplementary Fig. 26e.
Supplementary Table 38
Raw dataset for Supplementary Fig. 27.
Supplementary Table 39
Raw dataset for Supplementary Fig. 28b,c.
Supplementary Table 40
Raw dataset for Supplementary Fig. 29a,b.
Supplementary Table 41
Raw dataset for Supplementary Fig. 29c.
Supplementary Table 42
Raw dataset for Supplementary Fig. 29d.
Supplementary Table 43
Raw dataset for Supplementary Fig. 30a,b.
Supplementary Fig. 1
Unprocessed fluorescence images of blood samples for Supplementary Fig. 18a.
Supplementary PDF 1
Unprocessed fluorescence images of organs for Supplementary Fig. 19.
Supplementary PDF 2
Unprocessed fluorescence images of lower limb bones for Supplementary Fig. 20.
Supplementary PDF 3
Unprocessed HE staining of lungs for Supplementary Fig. 28a.
Supplementary PDF 4
Unprocessed immunohistochemical staining of CD8 + T cells in lung tissues for Supplementary Fig. 28c.
Supplementary PDF 5
Unprocessed immunohistochemical staining of CD8 + T cells in tumour tissues for Supplementary Fig. 29d.
Source data
Source Data Fig. 1
Unprocessed TEM and cryo-EM images of OMVs for Fig. 1a.
Source Data Fig. 4
Unprocessed immunofluorescence images and western blots for Fig. 4c,d.
Source Data Fig. 5
Unprocessed immunofluorescence images and western blots for Fig. 5c,d.
Source Data Fig. 1
Raw dataset for Fig. 1b,e–g.
Source Data Fig. 2
Raw dataset for Fig. 2a–c,e–g,i,k.
Source Data Fig. 3
Raw dataset for Fig. 3a,b,d,e,g–i.
Source Data Fig. 4
Raw dataset for Fig. 4b,c,e,g–j.
Source Data Fig. 5
Raw dataset for Fig. 5b,e,g–j.
Source Data Extended Data Fig. 1
Raw dataset for Extended Data Fig. 1a–b,d–f.
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Liu, G., Ma, N., Cheng, K. et al. Bacteria-derived nanovesicles enhance tumour vaccination by trained immunity. Nat. Nanotechnol. 19, 387–398 (2024). https://doi.org/10.1038/s41565-023-01553-6
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DOI: https://doi.org/10.1038/s41565-023-01553-6
