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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies show promise in cancer treatment but have limited response rates.
• There is a critical need to identify novel immune checkpoints that regulate T cell function for improved cancer immunotherapy.

Purpose of the Study:

• To identify novel immune suppressors targeting T cells.
• To investigate the role of paired immunoglobulin-like type 2 receptor alpha (PILRα) as a potential immune checkpoint in cancer.

Main Methods:

• High-throughput screening was employed to identify tumor cell-expressed immune suppressors.
• PILRα's interaction with T cell surface antigen CD99 and its downstream signaling pathways (ZAP70/NFAT/IL-2/JAK/STAT) were investigated.
• The efficacy of a stalk-targeting anti-PILRα antibody, alone and in combination with anti-PD-1, was evaluated in preclinical cancer models.

Main Results:

• Paired immunoglobulin-like type 2 receptor alpha (PILRα) was identified as a tumor cell-expressed immune suppressor that inhibits T cell activation, proliferation, and effector functions.
• PILRα interacts with CD99 via O-glycosylated residues in its stalk region, suppressing key T cell signaling pathways.
• Blocking PILRα-CD99 interaction with an anti-PILRα antibody enhanced T cell-mediated antitumor immunity and suppressed tumor growth, demonstrating synergistic effects with anti-PD-1 therapy.

Conclusions:

• PILRα functions as a novel immune checkpoint that negatively regulates T cell-mediated antitumor responses.
• PILRα is highly expressed in various human cancers and associated with poor prognosis, highlighting its clinical relevance.
• Targeting PILRα represents a promising therapeutic strategy for enhancing cancer immunotherapy efficacy.