文章：

肿瘤细胞上的PILRα与T细胞表面蛋白CD99相互作用抑制抗肿瘤免疫

PILRα on tumor cells interacts with the T cell surface protein CD99 to suppress antitumor immunity 

原文发布日期：2025-05-01 

英文摘要：

Immune checkpoint blockade using anti-programmed cell death protein 1/programmed cell death 1 ligand 1 antibody effectively targets the tumor-T cell interaction in cancer treatment, yet the overall response rate of less than 30% necessitates the identification of additional immune checkpoints modulating T cell function. Here, we identified the tumor cell-expressed paired immunoglobulin-like type 2 receptor alpha (PILRα) as an immune suppressor targeting T cells using high-throughput screening. PILRα inhibits T cell activation, proliferation and effector function by targeting CD99, a T cell surface antigen, suppressing ZAP70/NFAT/IL-2/JAK/STAT signaling. A cluster of O-glycosylated serine and threonine residues within the stalk region is critical for PILRα–CD99 interactions. Blocking these interactions with a stalk-targeting anti-PILRα antibody enhances T cell antitumor immunity and suppresses tumor growth. When combined with programmed cell death protein 1 antibody, anti-PILRα antibody shows synergistic tumor suppression. Notably, PILRα is highly expressed in several human cancers and predicts poor prognosis. These findings unveil PILRα as an immune checkpoint with therapeutic potential for clinical cancer immunotherapy. 

摘要翻译：

针对肿瘤与T细胞间相互作用的癌症治疗，使用抗程序细胞死亡蛋白1/程序细胞死亡1结合物1抗体能够有效抑制T细胞功能，然而整体应答率低于30%促使我们识别其他调节T细胞功能的免疫通路。在此研究中，我们通过高通量筛选发现肿瘤细胞表面配对免疫球蛋白型I类2受体α（PILRα）是一种针对T细胞作用力的抑制子。PILRα通过靶向CD99（一种T细胞表面抗原）抑制ZAP70/NFAT/IL-2/JAK/STAT信号通路，从而抑制T细胞激活、增殖及效应细胞功能。PILRα受体结合域内O-糖化丝氨酸和苏氨酸残基的聚集区是PILRα与CD99相互作用的关键。靶向PILRα受体的抗体阻断这些相互作用，增强T细胞对肿瘤的抗肿瘤免疫，并抑制肿瘤生长。与程序细胞死亡蛋白1抗体联合使用时，PILRα抗体显示出协同肿瘤抑制效果。值得注意的是，PILRα在几种人癌症中高度表达，并与不良预后相关。这些发现揭示了PILRα作为具有治疗潜力的免疫通路分子，为临床肿瘤免疫治疗开辟了新途径。 

原文链接：

https://www.nature.com/articles/s43018-025-00958-7