Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor...

Area of Science:

• Immunology
• Cancer Biology
• Biotechnology

Background:

• Cancer cells evade immune surveillance through mechanisms like aberrant glycosylation.
• Interferon-gamma (IFNγ) in the tumor microenvironment induces hypersialylation on cancer cells.
• Hypersialylation can lead to reduced T-cell effector function, potentially through receptors like Siglec-9.

Purpose of the Study:

• To investigate the role of IFNγ-induced hypersialylation in cancer immune evasion.
• To explore Siglec-9 as a T-cell checkpoint molecule and its impact on T-cell function.
• To develop novel engineered T cells targeting hypersialylated tumors for improved cancer immunotherapy.

Main Methods:

• Induction of hypersialylation in cancer cell lines using IFNγ.
• Analysis of Siglec-9 expression and function on T cells.
• CRISPR/Cas9 gene editing to knock out Siglec-9 in primary human T cells.
• Design and construction of Siglec-9-based chimeric switch receptors (CSRs).
• Evaluation of engineered T-cell function (cytokine secretion, activation markers) and anti-tumor activity in a xenograft model.

Main Results:

• IFNγ induces α2,6 hypersialylation in various cancer cell lines.
• Siglec-9+ T cells exhibit reduced effector function; Siglec-9 knockout enhances primary T-cell functionality.
• Siglec-9 CSR-transduced T cells show increased activation and cytokine production.
• Engineered T cells with Siglec-9 CSRs demonstrate significant anti-tumor efficacy in vivo.

Conclusions:

• Tumor hypersialylation, induced by IFNγ, represents a mechanism of immune evasion via Siglec-9.
• Targeting Siglec-9 with engineered T cells, such as those expressing Siglec-9 CSRs, can overcome this evasion.
• This approach offers a promising strategy for enhancing engineered T cell-based cancer therapy.