ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer-猫眼课题宝

DOI：

10.1101/2023.04.03.535346

发表时间：

2023-04

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Rebecca Garnham;D. Geh;Ryan Nelson;Erik Ramon-Gill;L. Wilson;Edward N Schmidt;Laura Walker;Beth Adamson;A. Buskin;A. Hepburn;Kirsty Hodgson;Hannah Kendall;F. Frame;N. Maitland;Kelly Coffey;C. Robson;D. Elliott;R. Heer;Matthew S Macauley;J. Munkley;L. Gaughan;J. Leslie;E. Scott

由于免疫抑制的前列腺癌肿瘤免疫微环境，免疫检查点阻断试验尚未在前列腺癌患者中作为单一疗法产生强有力的抗癌反应。ST3Gal1和其他唾液酸基转移酶通过合成唾液酸聚糖参与癌症和免疫抑制，唾液酸聚糖充当Siglec受体的配体。这些检查点对免疫反应很重要。然而，目前尚不清楚Siglec配体的合成是如何调节的，也几乎不知道唾液酸-Siglec轴在前列腺癌逃避抗肿瘤免疫中的作用。我们报道，在前列腺癌中，ST3Gal1水平与雄激素信号负相关。利用同基因小鼠模型，我们证明了ST3Gal1在调节肿瘤免疫逃避中发挥重要作用。利用小鼠模型、患者样本和体外模型，我们证明ST3Gal1合成唾液酸多糖，具有与Siglec-7和Siglec-9免疫受体结合的能力，阻止癌细胞的免疫清除。我们首次提供了Siglec-7/9配体及其各自的免疫受体在前列腺癌中表达的证据。重要的是，我们表明这些相互作用可以被苯扎鲁胺调节，并可能在苯扎鲁胺治疗的肿瘤中维持免疫抑制。我们的结论是，ST3Gal1的活性对前列腺癌的抗肿瘤免疫至关重要，并为晚期前列腺癌使用糖免疫检查点靶向治疗提供了理论基础。

Immune checkpoint blockade trials have yet to produce a robust anti-cancer response in prostate cancer patients as a monotherapy due to the immunosuppressed prostate cancer tumour immune microenvironment. ST3Gal1 and other sialyltransferases are implicated in cancer and immune suppression by synthesizing sialoglycans, which act as ligands for Siglec receptors. These checkpoints are important for the immune response. However, it’s unclear how the synthesis of Siglec ligands is regulated, and little is known about the role of sialoglycan-Siglec-axis in prostate cancer’s evasion of anti-tumour immunity. We report that ST3Gal1 levels negatively correlate with androgen signalling in prostate tumours. Utilising syngeneic mouse models, we demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion. Using mouse models, patient samples and in vitro models we show that ST3Gal1 synthesises sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. For the first time we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. Importantly, we show that these interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer

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