Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment

British Journal of Cancer volume 128, pages 1249–1266 (2023)Cite this article

Subjects

Abstract

Background

Tumour-derived small extracellular vesicles (sEVs) play a crucial role in cancer immunomodulation. In addition to tumour immune microenvironment, the peripheral immune system also contributes significantly to cancer progression and is essential for anticancer immunity. However, a comprehensive definition of which and how peripheral immune lineages are regulated by tumour-derived sEVs during cancer development remains incomplete.

Methods

In this study, we used mass cytometry with extensive antibody panels to comprehensively construct the systemic immune landscape in response to tumour development and tumour-derived sEVs.

Results

Systemic immunity was dramatically altered by tumour growth and tumour-derived sEVs. Tumour-derived sEVs significantly and extensively affected immune cell population composition as well as intracellular pathways, resulting in an immunosuppressive peripheral and tumour immune microenvironment, characterised by increased myeloid-derived suppressor cells and decreased Ly6C+CD8 T cells. These sEVs largely promoted hematopoietic recovery and accelerate the differentiation towards myeloid-derived suppressor cells. The knockdown of Rab27a reduced sEV secretion from tumour cells and delayed tumour growth and metastasis in vivo.

Conclusions

These results highlight that tumour-derived sEVs function as a bridge between peripheral immunity regulation and the tumour microenvironment, and contribute to cancer progression through altering the composition and function of the global immune macroenvironment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Immune cells in the spleen are significantly changed at non-metastatic stage of tumour development.
Fig. 2: Immune microenvironment in the bone marrow (BM) is reshaped at non-metastatic stage of tumour development.
Fig. 3: Immune cells in peripheral blood are dysregulated by tumour growth.
Fig. 4: Tumour-derived sEVs modify the tumour immune microenvironment.
Fig. 5: Intratumoral injection of tumour-derived sEVs leads to changes in systemic immunity.
Fig. 6: Increased circulating tumour-derived sEVs reshapes the immune system in the spleen.
Fig. 7: Increased circulating tumour-derived sEVs influence the BM microenvironment.
Fig. 8: Tumour-derived sEVs regulate the immune cell recovery and differentiation.
Fig. 9: Rab27a knockdown reduces the sEVs production and delay the tumour growth and metastases.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available upon reasonable request from the corresponding author (JW).

References

  1. Martin JD, Cabral H, Stylianopoulos T, Jain RK. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol. 2020;17:251–66.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Keam S, Gill S, Ebert MA, Nowak AK, Cook AM. Enhancing the efficacy of immunotherapy using radiotherapy. Clin Transl Immunol. 2020;9:e1169.

    Article  Google Scholar 

  3. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335–7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019;94:S3–S9.

    Article  CAS  PubMed  Google Scholar 

  5. Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52:17–35.

    Article  CAS  PubMed  Google Scholar 

  6. Pitt JM, Vetizou M, Daillere R, Roberti MP, Yamazaki T, Routy B, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016;44:1255–69.

    Article  CAS  PubMed  Google Scholar 

  7. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21:345–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014;16:717–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci USA. 2015;112:E566–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Allen BM, Hiam KJ, Burnett CE, Venida A, DeBarge R, Tenvooren I, et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat Med. 2020;26:1125–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20:485–503.

    Article  CAS  PubMed  Google Scholar 

  13. Cane S, Ugel S, Trovato R, Marigo I, De Sanctis F, Sartoris S, et al. The endless saga of monocyte diversity. Front Immunol. 2019;10:1786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E, Van Valckenborgh E, et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood. 2014;124:555–66.

    Article  CAS  PubMed  Google Scholar 

  16. Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol. 2018;35:69–79.

    Article  CAS  PubMed  Google Scholar 

  17. Zhou W, Zhou Y, Chen X, Ning T, Chen H, Guo Q, et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials. 2021;268:120546.

    Article  CAS  PubMed  Google Scholar 

  18. Wang J, De Veirman K, Faict S, Frassanito MA, Ribatti D, Vacca A, et al. Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. J Pathol. 2016;239:162–73.

    Article  CAS  PubMed  Google Scholar 

  19. Tu C, Du Z, Zhang H, Feng Y, Qi Y, Zheng Y, et al. Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells. Theranostics. 2021;11:2364–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang J, Zheng Y, Zhao M. Exosome-based cancer therapy: implication for targeting cancer stem cells. Front Pharm. 2016;7:533.

    Google Scholar 

  21. Wang J, Tu C, Zhang H, Huo Y, Menu E, Liu J. Single-cell analysis at the protein level delineates intracellular signaling dynamic during hematopoiesis. BMC Biol. 2021;19:201.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Xu CX, Lee TJ, Sakurai N, Krchma K, Liu F, Li D, et al. ETV2/ER71 regulates hematopoietic regeneration by promoting hematopoietic stem cell proliferation. J Exp Med. 2017;214:1643–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.

    Article  CAS  PubMed  Google Scholar 

  24. Riches A, Campbell E, Borger E, Powis S. Regulation of exosome release from mammary epithelial and breast cancer cells - a new regulatory pathway. Eur J Cancer. 2014;50:1025–34.

    Article  CAS  PubMed  Google Scholar 

  25. Rosell R, Wei J, Taron M. Circulating microRNA signatures of tumor-derived exosomes for early diagnosis of non-small-cell lung cancer. Clin Lung Cancer. 2009;10:8–9.

    Article  CAS  PubMed  Google Scholar 

  26. Wang J, Tu C, Zhang H, Zhang J, Feng Y, Deng Y, et al. Loading of metal isotope-containing intercalators for mass cytometry-based high-throughput quantitation of exosome uptake at the single-cell level. Biomaterials. 2020;255:120152.

    Article  CAS  PubMed  Google Scholar 

  27. Tirosh I, Izar B, Prakadan SM, Wadsworth MH 2nd, Treacy D, Trombetta JJ, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352:189–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang J, Zheng Y, Tu C, Zhang H, Vanderkerken K, Menu E, et al. Identification of the immune checkpoint signature of multiple myeloma using mass cytometry-based single-cell analysis. Clin Transl Immunol. 2020;9:e01132.

    Article  Google Scholar 

  29. Chevrier S, Levine JH, Zanotelli VRT, Silina K, Schulz D, Bacac M, et al. An immune atlas of clear cell renal cell carcinoma. Cell. 2017;169:736–749.e718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384:1455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Che Y, Yang Y, Suo J, An Y, Wang X. Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer. Cancer Immunol Immunother. 2020;69:2651–64.

    Article  CAS  PubMed  Google Scholar 

  32. Du Z, Feng Y, Zhang H, Liu J, Wang J. Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation. Cancer Lett. 2022;545:215841.

    Article  CAS  PubMed  Google Scholar 

  33. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166:678–89.

    Article  CAS  PubMed  Google Scholar 

  34. Kersten K, Coffelt SB, Hoogstraat M, Verstegen NJM, Vrijland K, Ciampricotti M, et al. Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1beta in tumor-associated macrophages. Oncoimmunology. 2017;6:e1334744.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30.

    Article  CAS  PubMed  Google Scholar 

  38. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.

    Article  CAS  PubMed  Google Scholar 

  39. Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14:195–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, et al. Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis. 2005;35:169–73.

    Article  CAS  PubMed  Google Scholar 

  42. Wada J, Onishi H, Suzuki H, Yamasaki A, Nagai S, Morisaki T, et al. Surface-bound TGF-beta1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions. Anticancer Res. 2010;30:3747–57.

    CAS  PubMed  Google Scholar 

  43. Hanninen A, Maksimow M, Alam C, Morgan DJ, Jalkanen S. Ly6C supports preferential homing of central memory CD8+ T cells into lymph nodes. Eur J Immunol. 2011;41:634–44.

    Article  PubMed  Google Scholar 

  44. Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol. 2011;11:645–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Piranlioglu R, Lee E, Ouzounova M, Bollag RJ, Vinyard AH, Arbab AS, et al. Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model. Nat Commun. 2019;10:1430.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hamada S, Masamune A, Shimosegawa T. Alteration of pancreatic cancer cell functions by tumor-stromal cell interaction. Front Physiol. 2013;4:318.

    PubMed  PubMed Central  Google Scholar 

  47. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest. 2010;120:457–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc Natl Acad Sci USA. 2014;111:4221–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yao X, Tu Y, Xu Y, Guo Y, Yao F, Zhang X. Endoplasmic reticulum stress-induced exosomal miR-27a-3p promotes immune escape in breast cancer via regulating PD-L1 expression in macrophages. J Cell Mol Med. 2020;24:9560–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lu C, Shi W, Hu W, Zhao Y, Zhao X, Dong F, et al. Endoplasmic reticulum stress promotes breast cancer cells to release exosomes circ_0001142 and induces M2 polarization of macrophages to regulate tumor progression. Pharm Res. 2022;177:106098.

    Article  CAS  Google Scholar 

  53. Feng L, Weng J, Yao C, Wang R, Wang N, Zhang Y, et al. Extracellular vesicles derived from SIPA1(high) breast cancer cells enhance macrophage infiltration and cancer metastasis through myosin-9. Biology. 2022;11:543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ham S, Lima LG, Chai EPZ, Muller A, Lobb RJ, Krumeich S, et al. Breast cancer-derived exosomes alter macrophage polarization via gp130/STAT3 signaling. Front Immunol. 2018;9:871.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Xie F, Zhou X, Su P, Li H, Tu Y, Du J, et al. Breast cancer cell-derived extracellular vesicles promote CD8(+) T cell exhaustion via TGF-beta type II receptor signaling. Nat Commun. 2022;13:4461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jiang M, Zhang W, Zhang R, Liu P, Ye Y, Yu W, et al. Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer. Oncogene. 2020;39:4681–94.

    Article  CAS  PubMed  Google Scholar 

  57. Owen KL, Brockwell NK, Parker BS. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression. Cancers. 2019;11:2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Aqdas M, Sung MH. NF-kappaB dynamics in the language of immune cells. Trends Immunol. 2023;44:32–43.

    Article  CAS  PubMed  Google Scholar 

  59. Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol. 2010;185:6413–9.

    Article  CAS  PubMed  Google Scholar 

  60. Mafi S, Mansoori B, Taeb S, Sadeghi H, Abbasi R, Cho WC, et al. mTOR-mediated regulation of immune responses in cancer and tumor microenvironment. Front Immunol. 2021;12:774103.

    Article  CAS  PubMed  Google Scholar 

  61. Haftcheshmeh SM, Abedi M, Mashayekhi K, Mousavi MJ, Navashenaq JG, Mohammadi A, et al. Berberine as a natural modulator of inflammatory signaling pathways in the immune system: focus on NF-kappaB, JAK/STAT, and MAPK signaling pathways. Phytother Res. 2022;36:1216–30.

    Article  CAS  PubMed  Google Scholar 

  62. Zerial M, McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001;2:107–17.

    Article  CAS  PubMed  Google Scholar 

  63. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012;72:4920–30.

    Article  CAS  PubMed  Google Scholar 

  64. Zhang F, Li R, Yang Y, Shi C, Shen Y, Lu C, et al. Specific decrease in B-cell-derived extracellular vesicles enhances post-chemotherapeutic CD8(+) T cell responses. Immunity. 2019;50:738–750.e737.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Basic and Applied Basic Research Foundation of Guangzhou Municipality (Project No. 202102020428 and 202201011861), the National Natural Science Foundation of China (Grant No. 82100224), the Tertiary Education Scientific Research Project of Guangzhou Municipal Education Bureau (Project No. 202235397), and the Key Discipline of Guangzhou Education Bureau (Basic Medicine) (Project No. 201851839).

Author information

Author notes

  1. These authors contributed equally: Zhimin Du, Hui Zhang

Authors and Affiliations

  1. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China

    Zhimin Du, Hui Zhang, Yueyuan Feng, Dewen Zhan, Shuya Li, Chenggong Tu, Jinbao Liu & Jinheng Wang

  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China

    Zhimin Du, Hui Zhang, Yueyuan Feng, Dewen Zhan, Shuya Li, Chenggong Tu, Jinbao Liu & Jinheng Wang

  3. School of Nursing, Guangzhou Medical University, 510182, Guangzhou, China

    Zhimin Du

Authors
  1. Zhimin Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yueyuan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dewen Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuya Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chenggong Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinbao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JW and JL conceived the idea and supervised the overall project. JW, HZ, YF and CT implemented the animal experiments with helps from DZ and SL. ZD and JW performed the mass cytometry experiments, analysed the data, and wrote the manuscript with suggestions from all authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinbao Liu or Jinheng Wang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, Z., Zhang, H., Feng, Y. et al. Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment. Br J Cancer 128, 1249–1266 (2023). https://doi.org/10.1038/s41416-023-02175-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02175-4

This article is cited by

Search

Advanced search

Quick links