Enhanced Th9-Mediated Adoptive Cell Therapy Against Mouse Melanoma Through GPR34/LPS1 Inverse Agonist Modulation

ABSTRACT: Th9 is a relatively new type of CD4+ T-cell subset that exhibits stronger anti-tumor immunity compared to other Th cell subsets. However, the potential of Th9-based adoptive cell therapy (ACT) is largely constrained by its low differentiation efficiency and short-lived nature. GPR34 (also known as LPS1) is the first identified lysophosphatidylserine (lysoPS) G-protein-coupled receptor (GPCR) and has been shown to regulate immune responses in various immune cells. Herein, we identified GPR34 inverse agonist molecules that significantly enhanced Th9 cell differentiation and improved the anti-tumor effectiveness of Th9-mediated ACT against mouse melanoma, which was verified as GPR34 dependent by GPR34-/- mice model. Notably, inverse agonism of GPR34 selectively activated MAPK-ERK pathway for IL9 production, but merely antagonism did not. A structure-based functional switching approach to design GPR34 inverse agonist from antagonist was realized and its rationality of underlying molecular basis was elucidated by in silico modelling study. Finally, inverse agonist 23 emerged as a promising candidate, highlighting GPR34 as a potential target for developing Th9-based immunotherapy for solid tumors in clinical settings.

ORGANISM(S): Mus musculus

PROVIDER: GSE286878 | GEO | 2026/09/30

REPOSITORIES: GEO