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Cellular and Molecular Biology

Immunosuppressive effect of small extracellular vesicle PD-L1 is restricted by co-expression of CD80

British Journal of Cancer volume 129, pages 925–934 (2023)Cite this article

Subjects

Abstract

Background

The PD-L1 on tumor cell-derived small extracellular vesicles (sEVs) can suppress the proliferation and cytokine production of T cells. However, PD-L1 can also be expressed by non-tumor cells. The present study is designed to test whether immunocytes release immunosuppressive PD-L1-positive sEVs.

Methods

sEVs were isolated from different clinical samples of head and neck squamous cell carcinoma (HNSCC) patients, the level and cellular origins of PD-L1-positive sEVs were assessed. Co-expression of CD80 on PD-L1-positive sEVs was examined to evaluate the immunosuppressive and tumor-promotive effects.

Results

PD-L1-positive sEVs in HNSCC patients had various cellular origins, including tumor cell, T cell, B cell, dendritic cell and monocyte/macrophage. However, PD-L1-positive sEVs derived from immune cells did not exert immunosuppressive functions due to the co-expression of CD80. It was verified that co-expression of CD80 disrupted the binding of sEV PD-L1 to its receptor PD-1 on T cells and attenuated the immunosuppression mediated by sEV PD-L1 both in vitro and in vivo.

Conclusion

The study suggests that PD-L1-positive sEVs have the cellular origin and functional heterogeneity. Co-expression of CD80 could restrict the immunosuppressive effect of sEV PD-L1. A greater understanding of PD-L1-positive sEV subsets is required to further improve their clinical application.

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Fig. 1: Presence of PD-L1-positive sEVs in both HD and HNSCC patients.
Fig. 2: PD-L1-positive sEVs secreted by immunocytes in patients and in vitro.
Fig. 3: Different clinical significance between tumor cell- and immunocyte-derived PD-L1-positive sEVs.
Fig. 4: PD-L1-positive I-sEVs did not suppress T cells in vitro.
Fig. 5: Co-expression of CD80 on sEVs disrupted PD-L1-positive sEV-mediated PD-1 binding and T cell inhibition.
Fig. 6: Co-expression of CD80 suppressed PD-L1-positive sEV-induced immunosuppression and tumor progression in melanoma model.

Data availability

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

References

  1. Dong H, Strome S, Salomao D, Tamura H, Hirano F, Flies D, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    Article  CAS  PubMed  Google Scholar 

  2. Poggio M, Hu T, Pai C, Chu B, Belair C, Chang A, et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell. 2019;177:414–27.e413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen G, Huang A, 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 

  4. Robbins P, Morelli A. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14:195–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cordonnier M, Nardin C, Chanteloup G, Derangere V, Algros M, Arnould L, et al. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J Extracell Vesicles. 2020;9:1710899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Serratì S, Guida M, Di Fonte R, De Summa S, Strippoli S, Iacobazzi R, et al. Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma. Mol Cancer. 2022;21:20.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Timaner M, Kotsofruk R, Raviv Z, Magidey K, Shechter D, Kan T, et al. Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1. Oncogene. 2020;39:187–203.

    Article  CAS  PubMed  Google Scholar 

  8. Li M, Soder R, Abhyankar S, Abdelhakim H, Braun M, Trinidad C, et al. WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1. J Extracell Vesicles. 2021;10:e12067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Keir M, Butte M, Freeman G, Sharpe A. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  10. Herbst R, Soria J, Kowanetz M, Fine G, Hamid O, Gordon M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Theodoraki M, Hoffmann T, Whiteside T. Separation of plasma-derived exosomes into CD3 and CD3 fractions allows for association of immune cell and tumour cell markers with disease activity in HNSCC patients. Clin Exp Immunol. 2018;192:271–83.

    Article  CAS  PubMed  Google Scholar 

  12. Sugiura D, Maruhashi T, Okazaki I, Shimizu K, Maeda T, Takemoto T, et al. cisRestriction of PD-1 function by -PD-L1/CD80 interactions is required for optimal T cell responses. Science. 2019;364:558–66.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao Y, Lee C, Lin C, Gassen R, Xu X, Huang Z, et al. PD-L1:CD80 Cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity. 2019;51:1059–73.e1059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stein J, Lipson E, Cottrell T, Forde P, Anders R, Cimino-Mathews A, et al. Pan-tumor pathologic scoring of response to PD-(L)1 blockade. Clin Cancer Res. 2020;26:545–51.

    Article  CAS  PubMed  Google Scholar 

  15. Tian Y, Ma L, Gong M, Su G, Zhu S, Zhang W, et al. Protein profiling and sizing of extracellular vesicles from colorectal cancer patients via flow cytometry. ACS Nano. 2018;12:671–80.

    Article  CAS  PubMed  Google Scholar 

  16. Cohen E. Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2006;24:2659–65.

    Article  CAS  PubMed  Google Scholar 

  17. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12:3–20.

    Article  PubMed  Google Scholar 

  18. Zhao Y, Harrison D, Song Y, Ji J, Huang J, Hui E. Antigen-presenting cell-intrinsic PD-1 neutralizes PD-L1 in cis to attenuate PD-1 signaling in T cells. Cell Rep. 2018;24:379–90.e376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chaudhri A, Xiao Y, Klee A, Wang X, Zhu B, Freeman G. In CisPD-L1 binds to B7-1 only on the same cell surface. Cancer Immunol Res. 2018;6:921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Haile S, Bosch J, Agu N, Zeender A, Somasundaram P, Srivastava M, et al. Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol. 2011;186:6822–9.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang W, Zhong W, Wang B, Yang J, Yang J, Yu Z, et al. ICAM-1-mediated adhesion is a prerequisite for exosome-induced T cell suppression. Dev Cell. 2022;57:329–43.e327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen L, Flies D. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sharpe A, Pauken K. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.

    Article  CAS  PubMed  Google Scholar 

  24. Sugiura D, Okazaki I, Maeda T, Maruhashi T, Shimizu K, Arakaki R, et al. PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity. Nat Immunol. 2022;23:399–410.

    Article  CAS  PubMed  Google Scholar 

  25. Wang S, Shi Y. Exosomes derived from immune cells: the new role of tumor immune microenvironment and tumor therapy. Int J Nanomedicine. 2022;17:6527–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Choi S, Cho H, Yea K, Baek M. Immune cell-derived small extracellular vesicles in cancer treatment. BMB Rep. 2022;55:48–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qiu Y, Yang Y, Yang R, Liu C, Hsu J, Jiang Z, et al. Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer. Oncogene. 2021;40:4992–5001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang X, Shen H, He Q, Tian W, Xia A, Lu X. Exosomes derived from exhausted CD8 + T cells impaired the anticancer function of normal CD8 + T cells. J Med Genet. 2019;56:29–31.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Key R&D Program of China (2019YFA0210500), National Natural Science Foundation of China (82341023, 81922038, 81801842), Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018005), The Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20212300), The Fundamental Research Funds for the Central Universities (2042022dx0003).

Author information

Author notes

  1. These authors contributed equally: Jin-Yuan Liu, Zi-Li Yu.

Authors and Affiliations

  1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, 430079, Wuhan, China

    Jin-Yuan Liu, Zi-Li Yu, Qiu-Yun Fu, Lin-Zhou Zhang, Jin-Bang Li, Min Wu, Bing Liu & Gang Chen

  2. Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China

    Zi-Li Yu, Bing Liu & Gang Chen

  3. TaiKang Center for Life and Medical Sciences, Wuhan University, 430071, Wuhan, China

    Gang Chen

  4. Frontier Science Center for Immunology and Metabolism, Wuhan University, 430071, Wuhan, China

    Gang Chen

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Contributions

GC conceived and designed the study. JYL, ZLZ, QYF and JBL performed the experiments. JYL, ZLY, MW and BL analyzed and interpreted the data. GC, JYL and ZLY wrote and edited the manuscript. All authors approved the final version of this manuscript.

Corresponding author

Correspondence to Gang Chen.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of School and Hospital of Stomatology, Wuhan University (IRB no.2022.B05) and Zhongnan Hospital of Wuhan University (IRB no. 2021059 K). Participants gave informed consent to participate in the study before taking part. The permission for animals was approved by the Institutional Research Ethics Committee of School and Hospital of Stomatology, Wuhan University (IRB no. S07921060C).

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Liu, JY., Yu, ZL., Fu, QY. et al. Immunosuppressive effect of small extracellular vesicle PD-L1 is restricted by co-expression of CD80. Br J Cancer 129, 925–934 (2023). https://doi.org/10.1038/s41416-023-02369-w

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