Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer

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 repres...

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Published in:	Cell reports (Cambridge) Vol. 43; no. 4; p. 114041
Main Authors:	Mishra, Alok K., Ye, Tianyi, Banday, Shahid, Thakare, Ritesh P., Su, Chinh Tran-To, Pham, Ngoc N.H., Ali, Amjad, Kulshreshtha, Ankur, Chowdhury, Shreya Roy, Simone, Tessa M., Hu, Kai, Zhu, Lihua Julie, Eisenhaber, Birgit, Deibler, Sara K., Simin, Karl, Thompson, Paul R., Kelliher, Michelle A., Eisenhaber, Frank, Malonia, Sunil K., Green, Michael R.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-04-2024 Elsevier
Subjects:	Acyltransferases Amidohydrolases - genetics Amidohydrolases - metabolism aminopeptidase inhibitors Animals bestatin CD24 CD24 Antigen - metabolism Cell Line, Tumor CP: Cancer CRISPR Female Glycosylphosphatidylinositols - metabolism GPAA1 Humans immune checkpoint immunotherapy Macrophages - immunology Macrophages - metabolism Mice ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - immunology Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Phagocytosis phagocytosis CRISPR ovarian cancer GPAA1 aminopeptidase inhibitors CP: Cancer immunotherapy immune checkpoint bestatin CD24
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Summary:	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. [Display omitted] •GPAA1 promotes cell surface expression of the anti-phagocytic signal CD24•GPAA1 knockout enhances macrophage-mediated phagocytosis of ovarian cancer cells•GPAA1 knockout suppresses growth of ovarian tumors in mice xenografts•Bestatin, an aminopeptidase inhibitor, inhibits GPAA1 and suppresses tumor growth Mishra et al. identify the GPI transamidase complex subunit GPAA1 as a factor required for cell surface expression of CD24 and show that genetic or pharmacological inhibition of GPAA1 enhances macrophage-mediated phagocytosis and suppresses ovarian tumor growth in mice. Their results highlight a potential immunotherapeutic approach for CD24+ ovarian cancers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2024.114041