Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells

Vasyl Eisenberg, Shiran Hoogi, Erel Katzman, Nimrod Ben Haim, Raphaelle Zur-Toledano, Maria Radman, Yishai Reboh, Oranit Zadok, Iris Kamer, Jair Bar, Irit Sagi, Ayal Hendel, Cyrille J. Cohen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1380-1391
Number of pages12
JournalCancer Immunology Research
Volume12
Issue number10
DOIs
StatePublished - 1 Oct 2024

All Science Journal Classification (ASJC) codes

  • General Medicine

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