Simin, K. | bioRxiv Science

bioRxiv2023

Inhibiting the GPI Transamidase Subunit GPAA1 Abolishes CD24 Surface Localization and Enhances Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

The CD24-Siglec10 signaling axis is an immune checkpoint pathway that shields ovarian cancer cells from phagocytosis by tumor-associated macrophages (TAMs), making it an appealing immunotherapeutic target. Here, we investigate factors influencing CD24 cell surface expression and assess their suitability as drug targets. Using a CRISPR-based knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment-1) as a positive regulator of CD24 cell surface expression. GPAA1 is a crucial component of the multi-subunit GPI transamidase complex, which facilitates the attachment of GPI lipid anchor to the C-terminus of CD24, enabling its surface localization. Reducing the activity of GPAA1 in ovarian cancer cells, either by genetic ablation or targeting with an aminopeptidase inhibitor bestatin, disrupts GPI attachment to CD24. This disruption impairs CD24 cell surface localization, enhances phagocytosis by TAMs, and suppresses tumor growth in mice. Our study highlights the potential of GPAA1 targeting as a therapeutic approach for CD24-positive ovarian cancers.

cancer biology↗

bioRxiv2022

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

cancer biology↗