Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models
Xiang Li, Yaru Li, Liang Dong, Yixin Chang, Xingying Zhang, Chunmeng Wang, Meixia Chen, Xiaochen Bo, Hebing Chen, Weidong Han, Jing Nie
Xiang Li, Yaru Li, Liang Dong, Yixin Chang, Xingying Zhang, Chunmeng Wang, Meixia Chen, Xiaochen Bo, Hebing Chen, Weidong Han, Jing Nie
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Research Article Immunology Oncology

Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models

Abstract

CD8+ exhausted T cells (Tex) are heterogeneous. PD-1 inhibitors reinvigorate progenitor Tex, which subsequently differentiate into irresponsive terminal Tex. The ability to maintain a capacity for durable proliferation of progenitor Tex is important, but the mechanism remains unclear. Here, we showed CD8+ progenitor Tex pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti–PD-1 treatment in vitro. Treatment with decitabine plus anti–PD-1 promoted the activation and expansion of tumor-infiltrated CD8+ progenitor Tex and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti–PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor Tex compared with anti–PD-1 monotherapy and restrained CD8+ T cell terminal differentiation. Strikingly, decitabine plus anti–PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8+ T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8+ progenitor Tex populations and improve responsiveness to anti–PD-1 therapy.

Authors

Xiang Li, Yaru Li, Liang Dong, Yixin Chang, Xingying Zhang, Chunmeng Wang, Meixia Chen, Xiaochen Bo, Hebing Chen, Weidong Han, Jing Nie

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Figure 5

scRNA-Seq of tumor infiltrated T cells.

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scRNA-Seq of tumor infiltrated T cells. (A) Graphical overview of the ex...
(A) Graphical overview of the experimental setting. The scRNA-Seq, paired scTCR-Seq, and bulk ATAC-Seq were applied to sorted tumor infiltrated CD3+ T cells in C, D, P, and DP groups. Downstream analysis includes DEG, clonotype, enriched TF, regulatory network, GO, and GSEA enrichment analysis. (B) t-distributed stochastic neighbor embedding (t-SNE) plot showing CD8+ T cells. Each dot for a single cell, colored by unsupervised cluster. (C) Dot plot showing expression of selected marker genes per cell type. The size of the dot encodes the ratio of cells that expressed the genes, and its color encodes the average expression level. (D) Bar plot showing the subtype proportion of CD8+ T cells per group. (E) Gene expression dynamics along the CD8+ Tex trajectory of cells in clusters 0, 1, and 4. PT, pseudotime; exp, expression.