A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice

Tal Gefen, Iris Castro, Darija Muharemagic, Yvonne Puplampu-Dove, Shradha Patel, Eli Gilboa

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors. In murine tumor immunotherapy models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity. In this issue of Molecular Therapy, Gefen et al. describe an oligonucleotide TIM-3-binding aptamer that was more effective than anti-TIM-3 antibody in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)2280-2288
Number of pages9
JournalMolecular Therapy
Volume25
Issue number10
DOIs
StatePublished - Oct 4 2017

Keywords

  • aptamer
  • cancer immunotherapy
  • TIM-3 aptamer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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