1. Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells.
- Author
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Eisenberg V, Hoogi S, Katzman E, Ben Haim N, Zur-Toledano R, Radman M, Reboh Y, Zadok O, Kamer I, Bar J, Sagi I, Hendel A, and Cohen CJ
- Subjects
- Humans, Animals, Mice, Sialic Acids metabolism, Antigens, CD metabolism, Cell Line, Tumor, Xenograft Model Antitumor Assays, Neoplasms immunology, Neoplasms therapy, Neoplasms metabolism, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Receptors, Chimeric Antigen genetics, CRISPR-Cas Systems, Tumor Microenvironment immunology, Sialic Acid Binding Immunoglobulin-like Lectins metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation. Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies. We focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9+ T-cell population displayed reduced effector function. We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system enhanced the functionality of primary human T cells. Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation. Thus, we designed several Siglec-9-based chimeric switch receptors (CSR), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen-specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers. Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors. Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell-based cancer treatment. See related Spotlight by Abken, p. 1310., (©2024 American Association for Cancer Research.)
- Published
- 2024
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