期刊
MOLECULAR THERAPY
卷 25, 期 10, 页码 2280-2288出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2017.06.023
关键词
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资金
- Dodson Interdisciplinary Immunotherapy Institute
- Sylvester Comprehensive Cancer Center, Medical School, University of Miami
T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-gamma (IFN-gamma) secreting CD4(+) T cells and CD8(+) T cyto-toxic 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.
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