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

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.