The response to anti-PD-1 and anti-LAG-3 checkpoint blockade is associated with regulatory T cell reprogramming.
Publication Title
Sci Transl Med
Document Type
Article
Publication Date
4-9-2025
Keywords
oregon; chiles
Abstract
Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, many patients develop therapeutic resistance. We previously identified and validated a pretreatment peripheral blood biomarker, characterized by a high frequency of LAG-3+ lymphocytes, that predicts resistance in patients receiving anti-PD-1 (aPD-1) ICB. To better understand the mechanism of aPD-1 resistance, we identified murine tumor models with a high LAG-3+ lymphocyte frequency (LAG-3hi), which were resistant to aPD-1 therapy, and LAG-3lo murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. LAG-3hi tumor-bearing mice were sensitive to aPD-1 + anti-LAG-3 (aLAG-3) therapy, and this benefit was CD8+ T cell dependent. The efficacy of combination therapy was enhanced in LAG-3hi (but not LAG-3lo) mice with depletion of CD4+ T cells. Furthermore, responses to aPD-1 + aLAG-3 correlated with regulatory T cell (Treg) phenotypic plasticity in LAG-3hi mice, suggesting a specific role for Tregs in response to aPD-1 + aLAG-3 treatment. Using Treg fate-tracking Foxp3GFP-Cre-ERT2 × ROSAYFP reporter mice, we demonstrated that expanded populations of unstable Tregs correlated with improved response to combination therapy in LAG-3hi mice. Complementing these preclinical data, an increased proportion of unstable Tregs also correlated with higher response rate and improved survival after aPD-1 + aLAG-3 therapy in a cohort of patients with metastatic melanoma (n = 117). These data indicate that Treg phenotypic plasticity affects aPD-1 + aLAG-3 responsiveness, which may represent a biomarker to aid patient selection and a rational therapeutic target for a subset of PD-1-refractory patients.
Area of Special Interest
Cancer
Specialty/Research Institute
Earle A. Chiles Research Institute
Specialty/Research Institute
Oncology
DOI
10.1126/scitranslmed.adk3702
