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Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer
Alok K Mishra1, Tianyi Ye1, Shahid Banday1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Abstract:
CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.
Insights
Researchers discovered GPAA1 (glycosylphosphatidylinositol anchor attachment 1) promotes CD24 expression in ovarian cancer, enabling immune evasion. Inhibiting GPAA1 with bestatin reduces CD24, enhances macrophage phagocytosis, and suppresses tumor growth, offering a new immunotherapy target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- CD24 overexpression in ovarian cancer facilitates immune evasion via Siglec10 interaction with macrophages.
- This
- don't eat me
- signal inhibits macrophage-mediated phagocytosis of tumor cells.
- Identifying factors regulating CD24 expression is crucial for developing novel ovarian cancer immunotherapies.
Purpose of the Study:
- To identify novel regulators of CD24 cell surface expression in ovarian cancer.
- To investigate the therapeutic potential of targeting these regulators for ovarian cancer immunotherapy.
Main Methods:
- Genome-wide CRISPR knockout screen to identify genes regulating CD24 expression.
- Genetic ablation of GPAA1 (glycosylphosphatidylinositol anchor attachment 1) and assessment of CD24 surface levels.
- Evaluation of macrophage-mediated phagocytosis and ovarian tumor growth in mouse models.
- Biochemical assays to assess bestatin's interaction with GPAA1 and its effect on GPI anchor attachment.
Main Results:
- GPAA1 was identified as a key positive regulator of CD24 cell surface expression.
- GPAA1 ablation led to abolished CD24 expression, enhanced macrophage phagocytosis, and inhibited tumor growth.
- Bestatin, an aminopeptidase inhibitor, binds GPAA1, blocks GPI attachment, reduces CD24 expression, and suppresses ovarian tumor growth.
Conclusions:
- GPAA1 is essential for CD24 cell surface expression and promotes ovarian cancer immune evasion.
- Targeting GPAA1 with inhibitors like bestatin represents a promising immunotherapeutic strategy for CD24-positive ovarian cancers.
