Degradation of tumour stromal hyaluronan by small extracellular vesicle-PH20 stimulates CD103+ dendritic cells and in combination with PD-L1 blockade boosts anti-tumour immunity

Yeonsun Hong, Yoon Kyoung Kim, Gi Beom Kim, Gi Hoon Nam, Seong A. Kim, Yoon Park, Yoosoo Yang, In San Kim

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43 Citations (Scopus)

Abstract

Highly accumulated hyaluronan (HA) not only provides a physiological barrier but also supports an immune-suppressive tumour microenvironment. High-molecular-weight (HMW)-HA inhibits the activation of immune cells and their access into tumour tissues, whereas, low-molecular-weight oligo-HA is known to potentially activate dendritic cells (DCs). In this paper, we investigated whether small extracellular vesicle (EVs)-PH20 hyaluronidase induces tumour HA degradation, which, in turn, activates DCs to promote anti-cancer immune responses. Informed by our previous work, we used a small EV carrying GPI-anchored PH20 hyaluronidase (Exo-PH20) that could deeply penetrate into tumour foci via HA degradation. We found that Exo-PH20-treatment successfully activates the maturation and migration of DCs in vivo, particularly CD103+ DCs leading to the activation of tumour-specific CD8+ T cells, which work together to inhibit tumour growth. Moreover, combination with anti-PD-L1 antibody provided potent tumour-specific CD8+ T cell immune responses as well as elicited prominent tumour growth inhibition both in syngenic and spontaneous breast cancer models, and this anti-tumour immunity was durable. Together, these results present new insights for HA degradation by Exo-PH20, providing a better understanding of oligo HA-triggered immune responses to cancer.

Original languageEnglish
Article number1670893
JournalJournal of Extracellular Vesicles
Volume8
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (2019R1A2B5B03004360 and 2017R1A3B1023418), the KU-KIST Graduate School of Converging Science and Technology Program, and the KIST Institutional Program.

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government [2019R1A2B5B03004360 and 2017R1A3B1023418]; the KIST Institutional Program; the KU-KIST Graduate School of Converging Science and Technology Program. This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (2019R1A2B5B03004360 and 2017R1A3B1023418), the KU-KIST Graduate School of Converging Science and Technology Program, and the KIST Institutional Program.

Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.

Keywords

  • Extracellular vesicle
  • cancer immunotherapy
  • dendritic cell
  • hyaluronan
  • hyaluronidase
  • immune checkpoint blockade

ASJC Scopus subject areas

  • Histology
  • Cell Biology

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