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 3

Administration of DP combination treatment inhibits tumor growth in vivo and reshapes tumor microenvironment.

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Administration of DP combination treatment inhibits tumor growth in vivo...
(A and B) C57BL/6J mice were transplanted with 1.5 × 105 MC38-OVA cells, treated with PBS (C group; black), or decitabine alone (0.2 mg/kg per mouse, days 7–9; D group, blue), or anti–PD-1 antibody alone (200 μg per mouse on days 12, 15, 18, and 21; P group, green) or decitabine plus anti–PD-1 (DP group, red) as indicated. Tumor sizes were examined every other day. (A) Shown are average and individual tumor growth curves (n = 6 per group). Data are represented as mean ± SEM, by 2-way ANOVA analysis. The number of mice in P and DP groups that acquired CR was shown. (B) Survival curves of each treatment group, by log-rank test. (C) C57BL/6J mice were implanted with 1 × 106 EG7-OVA cells, treatment scheme as in A. Tumor sizes were measured every 3 days. The average and individual tumor curves (n = 5 per group) are shown. Data are represented as mean ± SEM, by 2-way ANOVA analysis. (D) MC38 tumor samples as in A were collected on day 18, followed by CyTOF assay. T-SNE plot shows all CD45+ cells, colored by distinct immunocytes. (E) Absolute number of CD8+ TILs per 1 × 106 total cells in each group of MC38-OVA xenografts model on day 18 as in A. 1-way ANOVA analysis. (F) MC38-OVA-bearing mice were treated with decitabine (days 7–9) plus anti–PD-1 (days 12, 15, 18, and 21). Anti-CD8 or anti-CD4 antibody (200 μg per mouse) was administered twice a week starting on day 6. Shown are average tumor curves (n = 4 per group). 2-way ANOVA analysis. *P < 0.05; **P < 0.01; ***P < 0.001.