The GPR171 pathway suppresses T cell activation and limits antitumor immunity

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• G-protein-coupled receptor 171 (GPR171) and its ligand BigLEN are implicated in regulating food intake and anxiety.
• While GPR171 is a known T cell signature gene, its specific function in T cell immunity remains uninvestigated.

Purpose of the Study:

• To investigate the role of GPR171 in T cell function and immunity.
• To explore the therapeutic potential of targeting the GPR171/BigLEN axis in cancer immunotherapy.

Main Methods:

• Analysis of GPR171 transcription and protein expression in T cells.
• Investigating the effect of BigLEN on T cell receptor signaling and proliferation.
• Utilizing GPR171 knockout mice models.
• Assessing the impact of GPR171 antagonists on antitumor immunity and immune checkpoint blockade therapies.

Main Results:

• GPR171 is transcribed in T cells, with protein expression upregulated upon antigen stimulation.
• The GPR171/BigLEN interaction suppresses T cell receptor signaling and inhibits T cell proliferation.
• GPR171 deficiency in T cells results in heightened responses to antigen stimulation.
• GPR171 knockout mice demonstrate augmented antitumor immunity.
• GPR171 signaling blockade enhances T cell-mediated antitumor responses and improves outcomes with immune checkpoint blockade therapies.

Conclusions:

• The GPR171/BigLEN axis functions as a novel T cell checkpoint pathway.
• Targeting this pathway represents a promising strategy for enhancing cancer immunotherapy and overcoming treatment resistance.