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
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
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DOI：
10.1080/20013078.2019.1670893
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发表时间：
2019-12-01
影响因子：
16
通讯作者：
Kim, In-San
中科院分区：
文献类型：
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作者：
Hong, Yeonsun;Kim, Yoon Kyoung;Kim, In-San
高度积累的透明质酸（HA）不仅提供了生理屏障，而且还支持免疫抑制肿瘤微环境。高分子量（HMW）-HA抑制免疫细胞的活化及其进入肿瘤组织，而已知低分子量寡聚HA潜在地活化树突状细胞（DC）。在本文中，我们研究了小细胞外囊泡（EV）-PH 20透明质酸酶是否诱导肿瘤HA降解，从而激活DC以促进抗癌免疫应答。根据我们以前的工作，我们使用了一种携带GPI锚定的PH 20透明质酸酶（Exo-PH 20）的小型EV，该酶可以通过HA降解深入渗透到肿瘤病灶中。我们发现，Exo-PH 20处理成功地激活了体内DC的成熟和迁移，特别是CD 103（+）DC，导致肿瘤特异性CD 8（+）T细胞的激活，它们共同作用以抑制肿瘤生长。此外，与抗PD-L1抗体的组合提供了有效的肿瘤特异性CD 8（+）T细胞免疫应答，并在同系和自发性乳腺癌模型中引起显著的肿瘤生长抑制，并且这种抗肿瘤免疫是持久的。总之，这些结果为Exo-PH 20降解HA提供了新的见解，从而更好地理解了寡HA引发的对癌症的免疫反应。
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.