Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models
Xiang Li, … , Weidong Han, Jing Nie
Xiang Li, … , Weidong Han, Jing Nie
Published February 28, 2023
Citation Information: J Clin Invest. 2023;133(7):e165673. https://doi.org/10.1172/JCI165673.
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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 1

Low-dose decitabine-pretreated CD8+ T cells have increased cytotoxicity against tumors following anti–PD-1 treatment.

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Low-dose decitabine-pretreated CD8+ T cells have increased cytotoxicity ...
(A) Experimental timeline. Purified naive CD8+ T cells from TCROT-I mice were activated, treated with PBS (C), 10 nM decitabine (D), anti–PD-1 antibody (P) or the combination (DP), and cocultured with MC38-OVA-GFP cells at E: T ratio of 1:2 (A–C). (B) Frequency of live GFP+ MC38-OVA cells. Results are pooled from 2 experiments with n = 6 per group. 2-way ANOVA analysis. (C) Absolute number of CD8+ T cells (n = 3). 2-way ANOVA analysis. (D) PBS or decitabine-treated CD45.2+CD8+ TCROT-1 cells were transferred into MC38-OVA-bearing CD45.1+ C57BL/6J mice on day 12 when tumor size was below 200 mm3 (n = 6). Shown are average and individual tumor growth curves. Data are represented as mean ± SEM. 2-way ANOVA analysis. (E) PBS or decitabine-treated CD45.2+CD8+ TCROT-1 cells were transferred into MC38-OVA-bearing CD45.1+ C57BL/6J mice on day 12 when tumor size was between 200 and 400 mm3, followed by anti–PD-1 treatment as indicated (n = 5 per group). Shown are average and individual tumor growth curves. Data are represented as mean ± SEM. 2-way ANOVA analysis. (F) Experimental design. (G) Volcano plot showing DEGs of proliferating T cells between the DP group and the P group. Genes with Padj < 0.05 (2-sided unpaired Wilcoxon test, Bonferroni correction) and absolute log2 fold change (FC) ≥ 0.2 are identified as DEGs. Genes with Padj < 0.05 and absolute log2 FC ≥ 0.5 are labeled. (H) Heatmap showing scaled expression values of the indicated genes. Colors represent averaged z-scores of expression level. (I) GSEA of proliferating T cells generated by the immunologic signature gene sets of MSigDB. The 3 terms were from GSE369 and GSE41867. Colors of circles represent the normalized enrichment score (NES) calculated by GSEA for each signature. *P < 0.05; ***P < 0.001.