Transforming the Dark into Light: A Siglec-9 Switch
1Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany.
Abstract:
Tumor-associated immune repression dampens the success of T-cell therapy for cancer by a plethora of inhibitory mechanisms including aberrant glycosylation. In this issue, Eisenberg and colleagues show that IFNγ induces hyper-sialylation of cancer cells and that this acts as the "checkpoint" through binding to the inhibitory molecule Siglec-9 on immune cells. A chimeric Siglec-9 "switch" receptor converts the suppressive signal into a stimulatory signal, thereby restoring T-cell responses in the tumor tissue, which has multiple implications for the use of adoptive cell therapy in cancer. See related article by Eisenberg et al., p. 1380 (3).
Insights
Tumor cells use increased sialylation to suppress immune responses. Researchers developed a Siglec-9 "switch" receptor to convert this suppression into immune activation, enhancing T-cell therapy for cancer.
Area of Science:
- Immunology
- Cancer Biology
- Glycobiology
Background:
- Tumor-associated immune repression limits T-cell therapy efficacy.
- Aberrant glycosylation is a key mechanism of immune evasion in cancer.
Purpose of the Study:
- To investigate the role of aberrant glycosylation in tumor-induced immune suppression.
- To develop a novel strategy to overcome immune checkpoints in cancer therapy.
Main Methods:
- Analysis of IFNγ-induced hyper-sialylation in cancer cells.
- Development and testing of a chimeric Siglec-9 "switch" receptor.
- Evaluation of T-cell responses in tumor tissue.
Main Results:
- IFNγ induces cancer cell hyper-sialylation, creating an inhibitory checkpoint via Siglec-9.
- The Siglec-9 switch receptor effectively converts suppressive signals into stimulatory ones.
- Restored T-cell responses were observed in tumor tissues.
Conclusions:
- Targeting the Siglec-9/sialylation axis offers a promising strategy to enhance cancer immunotherapy.
- The Siglec-9 switch receptor has significant implications for adoptive cell therapy.
- Overcoming tumor immune evasion through engineered immune receptors is feasible.
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