Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor-based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid-binding immunoglobulin-like lectins) are expressed on immune cells and regulate immune responses and function. Siglec-7 and Siglec-9 contribute to immune evasion by interacting with their ligands. However, the role of Siglec-7/9 receptors and their ligands in prostate cancer remains poorly understood. Here, we find that Siglec-7 and Siglec-9 are associated with poor prognosis in prostate cancer patients, and are highly expressed in myeloid cells, including macrophages, in prostate tumor tissues. Siglecs-7 and -9 ligands were expressed in prostate cancer cells and human prostate tumor tissues. Blocking the interactions between Siglec-7/9 and sialic acids inhibited prostate cancer xenograft growth and increased immune cell infiltration in humanized mice in vivo. Using a CRISPRi screen and mass spectrometry, we identified CD59 as a candidate Siglec-9 ligand in prostate cancer. The identification of Siglecs-7 and -9 as potential therapeutic targets, including CD59/Siglec-9 axis, opens up opportunities for immune-based interventions in prostate cancer.

中文翻译：

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唾液酸化糖蛋白通过与前列腺癌中的 Siglec-7 和 Siglec-9 结合来抑制免疫细胞杀伤。


前列腺癌是美国男性癌症死亡的第二大原因。当前基于免疫检查点抑制剂的免疫疗法提高了许多恶性肿瘤的生存率;然而，它们未能延长前列腺癌的生存期。Siglecs（唾液酸结合免疫球蛋白样凝集素）在免疫细胞上表达并调节免疫反应和功能。Siglec-7 和 Siglec-9 通过与它们的配体相互作用来促进免疫逃避。然而，Siglec-7/9 受体及其配体在前列腺癌中的作用仍然知之甚少。在这里，我们发现 Siglec-7 和 Siglec-9 与前列腺癌患者的不良预后相关，并且在前列腺肿瘤组织的骨髓细胞（包括巨噬细胞）中高度表达。Siglecs-7 和 -9 配体在前列腺癌细胞和人前列腺肿瘤组织中表达。阻断 Siglec-7/9 和唾液酸之间的相互作用抑制了前列腺癌异种移植物的生长，并增加了体内人源化小鼠的免疫细胞浸润。使用 CRISPRi 筛选和质谱法，我们将 CD59 确定为前列腺癌中的候选 Siglec-9 配体。将 Siglecs-7 和 -9 确定为潜在的治疗靶点，包括 CD59/Siglec-9 轴，为前列腺癌的免疫干预提供了机会。