The response to anti–PD-1 and anti–LAG-3 checkpoint blockade is associated with regulatory T cell reprogramming
Annah S. Rolig, Xiyu Peng, Elizabeth R. Sturgill, Nisha Holay, Melissa J. Kasiewicz, Courtney Mick, Grace Helen McGee, William L. Miller, Yoshinobu Koguchi, Johanna Kaufmann, Niranjan Yanamandra, Sue Griffin, James Smothers, Matthew Adamow, Jasme Lee, Ronglai Shen, Margaret K. Callahan, William L. Redmond
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-3 hi ), which were resistant to aPD-1 therapy, and LAG-3 lo murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. LAG-3 hi 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-3 hi (but not LAG-3 lo ) mice with depletion of CD4 + T cells. Furthermore, responses to aPD-1 + aLAG-3 correlated with regulatory T cell (T reg ) phenotypic plasticity in LAG-3 hi mice, suggesting a specific role for T regs in response to aPD-1 + aLAG-3 treatment. Using T reg fate–tracking Foxp3 GFP-Cre-ERT2 × ROSA YFP reporter mice, we demonstrated that expanded populations of unstable T regs correlated with improved response to combination therapy in LAG-3 hi mice. Complementing these preclinical data, an increased proportion of unstable T regs 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 T reg 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.