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| Status |
Public on Jul 28, 2022 |
| Title |
Decitabine-induced T cell remodeling facilitates a high antitumor response to PD-1 blockade therapy by promoting the expansion and effector function of CD8+ progenitor exhausted T cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
CD8+ exhausted T (Tex) cells are heterogeneous with distinct transcriptional and epigenetic landscapes. PD-1 inhibitors reinvigorate progenitor Tex cells, which subsequently differentiate into irresponsive terminal Tex cells and impair the longlasting antitumor response of PD-1 blockade therapy. How to maintain durable proliferative capacity of progenitor Tex cells is important but remains largely unknown. Here, we showed that low-dose DNA demethylating agent decitabine-pretreated CD8+ progenitor Tex cells had enhanced cytolytic activity against tumors after anti-PD-1 treatment in vitro and could not reactivate the terminal Tex cells. Decitabine-plus-anti-PD-1 treatment promoted the activation and expansion of endogenous tumor-infiltrated CD8+ progenitor Tex cells and efficiently suppressed tumor growth in multiple mice tumor models. The single-cell RNA-sequencing, TCR-sequencing and ATAC-sequencing demonstrated that decitabine-plus-anti-PD-1 combination altered the transcriptional and epigenetic status of CD8+ Tex cells and markedly elevated the clonally expansion and effector function of progenitor Tex cells as compared with anti-PD-1 monotherapy, presenting increased expression of genes associated with T cell activation, proliferation, cytolytic activity, memory and mitochondrial metabolism. Strikingly, decitabine-plus-anti-PD-1 combination sustained the expression and activity of AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Suppressing JNK/AP-1 signaling in CD8+ T cells blunted decitabine-plus-anti-PD-1-induced activation of CD8+ T cells. Together, our findings show that the epigenetic therapy remodels CD8+ progenitor Tex subset, improves responsiveness to anti-PD-1 therapy and suppresses CD8+ T cell terminal differentiation.
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| Overall design |
scRNA-seq, scTCR-seq, ATAC-seq, and WGBS of T cells in the Control (C), decitabine(D), anti-PD-1(P), and decitabine-plus-anti-PD-1(DP) group.
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| Contributor(s) |
Nie J, Li X, Li Y, Chen H, Han W |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jul 28, 2022 |
| Last update date |
Aug 01, 2022 |
| Contact name |
Jing Nie |
| E-mail(s) |
niejing@301hospital.com.cn
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| Organization name |
Chinese PLA General Hospital
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| Street address |
No.28, Fuxing Road
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| City |
Beijing |
| State/province |
Beijing |
| ZIP/Postal code |
100853 |
| Country |
China |
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| Platforms (2) |
| GPL21273 |
HiSeq X Ten (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (24)
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| GSM6411749 |
DAC, scTCR-seq |
| GSM6411750 |
PD1, scRNA-seq |
| GSM6411751 |
PD1, scTCR-seq |
| GSM6411752 |
DP, scRNA-seq |
| GSM6411753 |
DP, scTCR-seq |
| GSM6411754 |
Con, ACT, scRNA-seq |
| GSM6411755 |
Con, ACT, scTCR-seq |
| GSM6411756 |
DAC, ACT, scRNA-seq |
| GSM6411757 |
DAC, ACT, scTCR-seq |
| GSM6411758 |
PD1, ACT, scRNA-seq |
| GSM6411759 |
PD1, ACT, scTCR-seq |
| GSM6411760 |
DP, ACT, scRNA-seq |
| GSM6411761 |
DP, ACT, scTCR-seq |
| GSM6411762 |
Con, replicate1, ATAC-seq |
| GSM6411763 |
Con, replicate2, ATAC-seq |
| GSM6411764 |
PD1, replicate1, ATAC-seq |
| GSM6411765 |
PD1, replicate2, ATAC-seq |
| GSM6411766 |
DP, replicate1, ATAC-seq |
| GSM6411767 |
DP, replicate2, ATAC-seq |
| GSM6411768 |
Con, WGBS |
| GSM6411769 |
DAC, WGBS |
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| Relations |
| BioProject |
PRJNA863246 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE209965_ACT_scTCR-seq_information.tar.gz |
1.3 Mb |
(ftp)(http) |
TAR |
| GSE209965_ATAC-seq_narrowPeak.tar.gz |
9.7 Mb |
(ftp)(http) |
TAR |
| GSE209965_RAW.tar |
1.0 Gb |
(http)(custom) |
TAR (of BEDGRAPH, TAR) |
| GSE209965_scTCR-seq_information.tar.gz |
1.8 Mb |
(ftp)(http) |
TAR |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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