Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade

作者：Michael Dixon, Lin Luo, Sadashib Ghosh, Jeffrey M Grimes, Jonathan D. Leavenworth, Jianmei W. Leavenworth, Jianmei W. Leavenworth, Jianmei W. Leavenworth · 发表于：Molecular Cancer · 年份：2021 · DOI：10.1186/s12943-021-01450-3 · 被引用次数：61 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、T-cell and B-cell Immunology

Abstract Background Accumulation of Foxp3 + regulatory T (Treg) cells in the tumor often represents an important mechanism for cancer immune evasion and a critical barrier to anti-tumor immunity and immunotherapy. Many tumor-infiltrating Treg cells display an activated phenotype and express the transcription factor Blimp1. However, the specific impact of these Blimp1 + Treg cells and their follicular regulatory T (T FR ) cell subset on tumor and the underlying mechanisms of action are not yet well-explored. Methods Various transplantable tumor models were established in immunocompetent wild-type mice and mice with a Foxp3-specific ablation of Blimp1. Tumor specimens from patients with metastatic melanoma and TCGA datasets were analyzed to support the potential role of Treg and T FR cells in tumor immunity. In vitro culture assays and in vivo adoptive transfer assays were used to understand how Treg, T FR cells and antibody responses influence tumor control. RNA sequencing and NanoString analysis were performed to reveal the transcriptome of tumor-infiltrating Treg cells and tumor cells, respectively. Finally, the therapeutic effects of anti-PD-1 treatment combined with the disruption of Blimp1 + Treg activity were evaluated. Results Blimp1 + Treg and T FR cells were enriched in the tumors, and higher tumoral T FR signatures indicated increased risk of melanoma metastasis. Deletion of Blimp1 in Treg cells resulted in impaired suppressive activity and a reprogramming into effec...