Newcastle University, Centre for Cancer, Newcastle University Biosciences Institute, Newcastle, NE1 3BZ, UK.
Newcastle University, Centre for Cancer, Newcastle University Translational and Clinical Research Institute, Newcastle, NE1 3BZ, UK.
Commun Biol. 2024 Mar 6;7(1):276. doi: 10.1038/s42003-024-05924-0.
Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. 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.
免疫检查点阻断在前列腺癌中尚未产生强大的抗癌反应。唾液酸转移酶已在包括乳腺癌、黑色素瘤、结直肠癌和前列腺癌在内的几种实体瘤中得到证实，通过合成唾液酸化糖链来促进免疫抑制，这些糖链作为 Siglec 受体的配体发挥作用。我们报告 ST3β-半乳糖苷α-2,3-唾液酸转移酶 1（ST3Gal1）水平与前列腺肿瘤中的雄激素信号呈负相关。我们证明 ST3Gal1 通过合成具有与 Siglec-7 和 Siglec-9 免疫受体结合能力的唾液酸化糖链，在调节肿瘤免疫逃逸方面发挥重要作用，从而防止癌细胞的免疫清除。在这里，我们提供了前列腺肿瘤中 Siglec-7/9 配体及其各自免疫受体表达的证据。这些相互作用可以被恩扎鲁胺调节，并可能在恩扎鲁胺治疗的肿瘤中维持免疫抑制。我们得出结论，ST3Gal1 的活性对前列腺癌抗肿瘤免疫至关重要，并为在晚期前列腺癌中使用糖免疫检查点靶向治疗提供了依据。
