Targeting PILRa, an immune checkpoint mediating T cell suppression, for cancer immunotherapy

One of the most successful therapies in cancer treatment involves immune checkpoint blockade using the anti-programmed death-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibody, which targets the interaction between tumors and T cells. However, the overall response rate is < 30% in patients with cancer. Therefore, there is an urgent need to identify additional immune checkpoints that can modulate T-cell function. In this study, we identified the tumor cell-expressed paired Ig-like type 2 receptor a (PILRa) as an immune suppressor that targets T cells, using a high-throughput screening approach. PILRa suppresses T-cell activation, proliferation, and effector function in both cultured cells and mouse xenograft and allograft models. It specifically targets CD99, a T cell surface antigen, to suppress the ZAP70/NFAT/IL2/JAK/STAT signaling in T cells. The cluster of O-glycosylated serine (Ser)/threonine (Thr) residues within the stalk region plays a critical role in PILRa–CD99 interactions, thereby influencing the immunosuppressive function of PILRa. Blocking interactions between PILRa and CD99 using an anti-PILRa antibody that targets the stalk region potently enhances T cell antitumor immunity and suppresses tumor growth. Additionally, when combined anti-PILRa with anti-PD-1 antibodies, synergistic effects on tumor suppression were observed. Notably, PILRa is highly expressed in various human cancers, and its expression levels serve as a predictive marker for poor prognosis in patients with cancer. Taken together, our results unveil PILRa as an immune checkpoint and highlight the promising therapeutic potential of targeting PILRa in clinical cancer immunotherapy. Overall design: RNA-seq performed in this study was designed to reveal the T cell gene expression regulated by PILRa