Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer
Alok K. Mishra,
Tianyi Ye,
Shahid Banday,
Ritesh P. Thakare,
Chinh Tran-To Su,
Ngoc N.H. Pham,
Amjad Ali,
Ankur Kulshreshtha,
Shreya Roy Chowdhury,
Tessa M. Simone,
Kai Hu,
Lihua Julie Zhu,
Birgit Eisenhaber,
Sara K. Deibler,
Karl Simin,
Paul R. Thompson,
Michelle A. Kelliher,
Frank Eisenhaber,
Sunil K. Malonia,
Michael R. Green
Affiliations
Alok K. Mishra
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author
Tianyi Ye
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Shahid Banday
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Ritesh P. Thakare
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Chinh Tran-To Su
Bioinformatics Institute (BII), Agency for Science, Technology, and Research (A∗STAR), 30 Biopolis Street, Matrix, #07-01, Singapore 138671, Singapore
Ngoc N.H. Pham
Faculty of Biology and Biotechnology, University of Science, Vietnam National University, 227 Nguyen Van Cu Street, District 5, Ho Chi Minh City, Vietnam
Amjad Ali
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Ankur Kulshreshtha
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Shreya Roy Chowdhury
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Tessa M. Simone
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Kai Hu
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Lihua Julie Zhu
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine and Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Birgit Eisenhaber
Bioinformatics Institute (BII), Agency for Science, Technology, and Research (A∗STAR), 30 Biopolis Street, Matrix, #07-01, Singapore 138671, Singapore; Lausitz Advanced Scientific Applications (LASA) gGmbH, Straße der Einheit 2–24, 02943 Weißwasser, Germany
Sara K. Deibler
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Karl Simin
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Paul R. Thompson
Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Michelle A. Kelliher
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Frank Eisenhaber
Bioinformatics Institute (BII), Agency for Science, Technology, and Research (A∗STAR), 30 Biopolis Street, Matrix, #07-01, Singapore 138671, Singapore; Lausitz Advanced Scientific Applications (LASA) gGmbH, Straße der Einheit 2–24, 02943 Weißwasser, Germany; School of Biological Sciences, Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore 637551, Singapore; Corresponding author
Sunil K. Malonia
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author
Michael R. Green
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
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.
