CD44+CD24-/low sphere-forming cells of EBV-associated gastric carcinomas show immunosuppressive effects and induce Tregs partially through production of PGE2.

Abstract

EBV-associated gastric carcinoma (EBVaGC) is accompanied by massive lymphocyte infiltration, but therapy resistance and tumor progression still occur in patients with EBVaGC. Cancer stem cells (CSCs) are reported to possess immunomodulatory ability that allows them to resist immune-mediated rejection for many tumor types. However, whether and how CSCs in EBVaGC exhibit immunosuppression has not yet been elucidated. We isolated CSC-like sphere-forming cells (SFCs) from EBVaGC cell line SNU-719 using the cancer sphere method. We validated their CSC-associated properties in the expression of the epithelial-mesenchymal transition (EMT)-related genes, the ability to form colonies, and resistance to chemotherapy drug-induced apoptosis and explored their immunomodulatory ability using the coculture system with PBMC (peripheral blood mononuclear cell). These CSC-like SFCs were CD44+CD24-/low and were more tumorigenic than the parental SNU-719 cells in the xenograft mouse model. Remarkably, in the tumor-PBMC co-culturing experiments, these EBVaGC SFCs demonstrated profound immunosuppression by inhibiting the proliferation of PBMCs and T cell activation as well as inducing the generation of regulatory T cells (Tregs). Furthermore, the induction of Tregs was partially dependent on prostaglandin E2 (PGE2) produced from SFCs. Moreover, the presence of high CD44+CD24-/low cells in tumor tissues predicted a decreased disease-free survival in patients with EBVaGC. Our study collectively confirmed the existence and immune resistance of CSCs in EBVaGC and offers new insights into the development of novel anti-EBVaGC strategies by targeting CSCs.

• Authors: Dayang Hui, Jianning Chen, Ye Jiang, Yuhang Pan, Zhigang Zhang, Min Dong, Chunkui Shao
• Journal: Experimental cell research (Exp Cell Res) Vol. 390 Issue 2 Pg. 111968 (05 15 2020) ISSN: 1090-2422 [Electronic] United States
• PMID: 32197932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• CD24 Antigen
• CD24 protein, human
• CD44 protein, human
• Hyaluronan Receptors
• Dinoprostone

Topics

• Adult
• Aged
• Animals
• CD24 Antigen (genetics, immunology)
• Carcinoma (complications, genetics, immunology, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Dinoprostone (biosynthesis, immunology)
• Epithelial-Mesenchymal Transition (genetics, immunology)
• Epstein-Barr Virus Infections (complications, genetics, immunology, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Herpesvirus 4, Human (immunology, pathogenicity)
• Humans
• Hyaluronan Receptors (genetics, immunology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Signal Transduction
• Spheroids, Cellular (immunology, pathology)
• Stomach Neoplasms (complications, genetics, immunology, pathology)
• T-Lymphocytes, Regulatory (immunology, pathology, virology)
• Xenograft Model Antitumor Assays