The response to anti–PD-1 and anti–LAG-3 checkpoint blockade is associated with regulatory T cell reprogramming Journal Article
| Authors: | Rolig, A. S.; Peng, X.; Sturgill, E. R.; Holay, N.; Kasiewicz, M.; Mick, C.; McGee, G. H.; Miller, W.; Koguchi, Y.; Kaufmann, J.; Yanamandra, N.; Griffin, S.; Smothers, J.; Adamow, M.; Lee, J.; Shen, R.; Callahan, M. K.; Redmond, W. L. |
| Article Title: | The response to anti–PD-1 and anti–LAG-3 checkpoint blockade is associated with regulatory T cell reprogramming |
| 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. Copyright © 2025 The Authors, some rights reserved. |
| Keywords: | survival; cancer survival; controlled study; protein expression; treatment response; unclassified drug; major clinical study; clinical trial; drug efficacy; nonhuman; flow cytometry; polymerase chain reaction; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cancer immunotherapy; melanoma; tumor volume; animal experiment; animal model; cohort analysis; drug effect; cell line, tumor; cancer therapy; mice, inbred c57bl; c57bl mouse; regulatory t lymphocyte; immunology; immune response; immunoglobulin g; t-lymphocytes, regulatory; cd4+ t lymphocyte; tumor cell line; tamoxifen; antigens, cd; tumor growth; penicillin derivative; lymphocyte; antibody; leukocyte antigen; peripheral blood mononuclear cell; nuclear reprogramming; programmed death 1 receptor; metastatic melanoma; clinical trial (topic); streptomycin; lymphocyte activation gene 3 protein; immune checkpoint inhibitor; cellular reprogramming; humans; human; female; article; programmed cell death 1 receptor; immune checkpoint inhibitors; malignant neoplasm; cd4 antibody; single cell rna seq; lag3 protein, human; nivolumab plus relatlimab; anti lag 3 monoclonal antibody; anti pd 1 monoclonal antibody; cd8 antibody; lag3 protein, mouse; regulatory t cell reprogramming |
| Journal Title: | Science Translational Medicine |
| Volume: | 17 |
| Issue: | 793 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2025-04-09 |
| Start Page: | eadk3702 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.adk3702 |
| PUBMED: | 40203085 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus |
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