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

Research output: Contribution to journalArticlepeer-review

5 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

Keywords

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

ASJC Scopus subject areas

  • Histology
  • Cell Biology

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