Abstract C059: GPC2: An immune checkpoint mediating natural killer cell evasion in MHC-I deficient tumours

Major histocompatibility complex class I (MHC-I) molecules enable cytotoxic T lymphocytes to recognize and eliminate malignant cells. Tumours that downregulate or lose MHC-I expression evade T-cell immunity but often develop additional mechanisms to suppress natural killer (NK) cell cytotoxicity. To identify regulators of NK cell resistance, we performed a genome-wide CRISPR-Cas9 loss-of-function screen in HLA null tumour cells and identified glypican-2 (GPC2) as a potent suppressor of NK cell activity. In colorectal cancer, GPC2 expression inversely correlated with HLA class I levels and NK infiltration, supporting its clinical relevance in immune evasion. Functionally, GPC2 impairs immunological synapse formation and NK-cell cytotoxicity, and drives a mesenchymal, stem-like phenotype marked by LGR5 upregulation. Significantly, our rationally designed stapled peptide, targeted GPC2 and restored NK cell cytotoxicity against HLA null cancers. These findings identify GPC2 as a critical mediator of NK cell immune escape and as a therapeutic target in MHC-I-deficient tumours. Citation Format: Gloryn Chia, Malini Rethnam, Sharmistha Kundu, Yi Ren, Oleg GRINCHUK, Kian Chee CHONG, Zhisheng HER, Yaw Sing Tan, Ker Kan Tan, Qingfeng Chen. GPC2: An immune checkpoint mediating natural killer cell evasion in MHC-I deficient tumours [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C059.