The response to anti–PD-1 and anti–LAG-3 checkpoint blockade is associated with regulatory T cell reprogramming
Menée à l'aide de modèles murins et à partir de données portant sur 117 patients atteints d'un mélanome métastatique, cette étude met en évidence une association entre la modification du phénotype des lymphocytes régulateurs et la réponse aux anti-PD1 et anti-LAG3
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.
Science Translational Medicine , résumé 2024