Cell Reports (Apr 2024)

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

Journal volume & issue
Vol. 43, no. 4
p. 114041

Abstract

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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.

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