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

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.

KEYWORDS:

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

Acknowledgments

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.

Author contributions

Y.Y. and I.-S.K. designed the experiments; Y.H., Y.K.K., G.B.K., G.-H.N., and S.A.K. performed the experiments; Y.H., Y.K.K., and Y.P. analysed the data and Y.H., Y.Y., and I.-S.K. wrote the manuscript.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

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.