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 8

DP treatment suppresses the terminal differentiation of exhausted T cells.

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DP treatment suppresses the terminal differentiation of exhausted T cell...
(A) t-SNE plot of CD8+ T cells colored by normalized expression of Jund. Exp, expression. (B) Boxplot showing T cell activation score calculated using the T cell activation (GO:0042110) gene set, 1-way ANOVA analysis. (C) Bar plot showing the NES from ranked list of genes expressed in proliferating T cells from ACT model in DP group and P group, calculated using GSEA. Gene signatures are from immunologic signature gene sets of MSigDB. (D and E) GSEA of indicated signatures (from GSE41867) from the ranked list of genes in proliferating T cells from ACT model in DP group versus P group. FDR, false discovery rate. (F) Boxplot showing T cell activation score from 4 groups of CD8+ TILs in cells with different JunD levels. Cells are divided into 4 groups, and groups 1, 2, 3, and 4 represent a quarter of cells with JunD expression levels from low to high. 1-way ANOVA analysis. (G) Purified naive CD8+ T cells from TCROT-I mice were activated, treated with PBS (C), anti–PD-1 (P), or decitabine plus anti–PD-1 (DP) as shown. Before coculture with MC38-OVA-GFP cells, the indicated T cells were incubated with JNK inhibitor JNK-IN-8 (50 nM, 100 nM), AP-1 inhibitor T-5224 (2 μM, 10 μM), or JNK activator anisomycin (0.5 μM, 1 μM) for 24 hours. These CD8+ T cells were then cocultured with MC38-OVA-GFP cells at an E-to-T ratio of 1:2. Frequencies of live GFP+ target cells are shown, by 1-way ANOVA analysis. (H) NC and JunD KO TCROT-I T cells were pretreated with decitabine, anti–PD-1, or the combination. Frequencies of live GFP+ MC38-OVA target cells after coculture with the indicated T cells at E-to-T ratio of 1:2 for 48 hours. 2-way ANOVA analysis. *P < 0.05; **P < 0.01; ***P < 0.001.