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Response to anti-PD-1 + anti-LAG-3 checkpoint blockade is associated with T regulatory cell functional reprogramming and instability

ABSTRACT: We previously identified and validated a pre-treatment peripheral blood biomarker, characterized by a high frequency of LAG-3+ lymphocytes, that predicts resistance in patients receiving anti-PD-1 immune checkpoint blockade. To better understand the mechanism of aPD-1 resistance and select rational therapies to overcome 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. As we hypothesized, LAG-3hi tumor-bearing mice were sensitive to aPD-1+aLAG-3 therapy and the benefit of combination therapy was CD8+ T cell-dependent. Unexpectedly, the benefit 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 significantly correlated with T regulatory cell (Treg) phenotypic plasticity in LAG-3hi mice, suggesting a specific role for Tregs in the mechanism of response to this combination. Using Treg fate tracking Foxp3GFP-Cre-ERT2 x ROSAYFP reporter mice we demonstrate that expanded populations of unstable Tregs correlate with response to combination therapy in LAG-3hi mice. Complementing this preclinical data, an increased proportion of unstable Tregs also significantly 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 is a key mechanism in aPD-1+aLAG-3 responsiveness, which may represent both a novel biomarker to aid patient selection and a rationale therapeutic target to expand benefit for a subset of PD-1 refractory patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE286358 | GEO | 2025/04/09

REPOSITORIES: GEO

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Project description:HPV-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced stage disease. Despite improved outcomes with PD-1 targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in pre-clinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either aPD-1 or the class I histone deacetylase (HDAC) inhibitor Entinostat. Mice bearing HPV16+, aPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either aPD-1 or Entinostat to determine anti-tumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and scRNAseq with TCR enrichment. Combination of HPV vaccine and NHS-IL12 with either Entinostat or aPD-1 yields significant anti-tumor activity and prolonged survival in aPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus aPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were parallelled by strong differentiation of tumor-associated macrophages (TAMs) towards proinflammatory, anti-tumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the pre-clinical findings was found to be associated with improved survival in patients with HPV-associated malignancies. Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.

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Response to anti-PD-1 + anti-LAG-3 checkpoint blockade is associated with T regulatory cell functional reprogramming and instability

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