Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

Area of Science:

• Immunology
• Cancer Therapy
• Cellular Biology

Background:

• Stimulator of Interferon Genes (STING) receptor ligands are explored as cancer therapy adjuvants.
• STING ligands are known to induce immunogenic cell death and enhance CD8 T-cell immunity.
• The impact of STING ligands on human γδ T cells remains uninvestigated.

Purpose of the Study:

• To investigate the effects of STING ligands on the activation and effector functions of tumor-reactive human γδ T cells.
• To explore the co-stimulatory and inhibitory effects of STING ligands on γδ T cell responses.
• To assess the impact of STING ligands on γδ T cell-mediated anti-tumor immunity.

Main Methods:

• Utilized cyclic dinucleotide and non-dinucleotide STING ligands (diABZI, MSA-2).
• Co-cultured ligands with peripheral blood mononuclear cells (PBMCs) and purified γδ T cells, including monocytes.
• Assessed cytokine induction (IL-1β, TNF-α), cell proliferation, cell death, STING pathway activation (TBK1/IRF3 phosphorylation, IP-10 secretion), and tumor cell killing (Real-Time Cell Analyzer).

Main Results:

• STING ligands co-stimulated cytokine induction in Vδ2 T cells but inhibited their proliferation.
• Monocytes were required for STING ligand-induced cytokine induction in purified γδ T cells.
• STING ligands induced significant IL-1β and TNF-α secretion in monocytes and triggered massive cell death in both γδ T cells and monocytes.
• STING activation varied in tumor cells, and STING ligands modulated Vδ2 T cell-mediated tumor cell killing with variable efficacy.

Conclusions:

• STING ligands exert complex regulatory effects on human γδ T cells in vitro.
• These findings highlight the dual role of STING ligands, potentially impacting γδ T cell immunotherapy efficacy.
• Further research is needed to define optimal conditions for utilizing STING ligands in γδ T cell-based cancer therapies.