The Evolutionary Trajectory and Prognostic Value of GITR+ Tregs Reprogramed by Tumor-Intrinsic PD-1/c-MET Signaling in Pancreatic Cancer.

Abstract

Tumor-intrinsic programmed cell death 1 (PD-1) has been shown to activate the mesenchymal epithelial transition factor (MET) pathway via its phosphorylation in pancreatic ductal adenocarcinoma (PDAC). However, the immunoregulatory consequences of MET activation remain poorly understood. Herein, a significant positive correlation between phosphorylated MET (p-MET) and tumor-intrinsic PD-1 is verified, both of which are independently associated with adverse prognosis. Elevated p-MET levels correlated with diminished CD8⁺ T cell cytotoxicity and increased regulatory T cell (Treg) infiltration. Single-cell RNA sequencing revealed MET activation selectively drives the accumulation of intratumoral GITR⁺ Tregs-a distinct effector Treg subset with potent immunosuppressive function and high prognostic relevance. Compared to KLF2⁺ naïve Tregs, GITR⁺ Tregs exhibited an activated phenotype and enhanced expression of immunoregulatory markers. Subgroup analysis further demonstrated that elevated GITR⁺ Treg infiltration diminished the prognostic utility of serum CA19-9, underscoring the immunosuppressive dominance of this Treg subset. Mechanistically, MET-IL-23-STAT4 axis orchestrates GITR⁺ Treg-mediated immune evasion in PDAC. In vivo, MET inhibition and GITR agonism synergize to enhance antitumor immunity in an orthotopic PDAC model. Collectively, these findings highlight MET signaling and GITR⁺ Tregs as actionable targets to counteract immune evasion and improve the efficacy of immunotherapeutic strategies in PDAC.