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| Status |
Public on Apr 07, 2021 |
| Title |
Dickkopf 1 Impairs Sensitivity to PD-1 Blockade through CD8+ T Cell Inactivation in dMMR/MSI Colorectal Cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Dickkopf 1 (DKK1) could promote tumor progression by suppressing immunity. Therefore, we investigated whether DKK1 influence prognosis and sensitivity to PD-1 blockade in colorectal cancers (CRCs) with defective DNA mismatch repair genes (dMMR) or microsatellite instability (MSI). We found that elevated DKK1 expression was associated with recurrence and dismissed CD8+ T cell infiltrations, and patients with high serum DKK1 had poor anti-PD-1 response. RNA interference or neutralization of DKK1 in CRCs enhanced CD8+ T cell cytotoxicity, and down-regulation of T-bet and E2F1 following GSK3β activation was detected in DKK1-treated CD8+ T cells. In organoid-lymphocyte co-culture model, apoptosis proportions were elevated after individual neutralization of both PD-1 and DKK1, and the combined neutralization resulted in further increases. In conclusion, DKK1 suppresses tumor immunity in dMMR/MSI CRCs by inactivating CD8+ T cells through GSK3β/E2F1/T-bet axis. DKK1 neutralization may improve the sensitivity to PD-1 blockade in dMMR/MSI CRCs.
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| Overall design |
We obtained tumor tissues and serum of dMMR/MSI CRCs. DKK1 expression and immune status of 80 cases were evaluated by immunohistochemistry, while serum DKK1 of another 43 cases receiving PD-1 blockade were measured by ELISA. Control and DKK1 knockdown CT26 cells were grafted in BALB/c mice, or co-cultured with T cells in vitro. Organoids of dMMR CRCs were co-cultured with T cells, treated with DKK1, anti-DKK1 and mock. PD-1 neutralizations were given to some of those models. To assess cytotoxicity of T cells, apoptosis assays and flow cytometrys were used. RNA sequencing on CD8+ T cells were performed to investigate downstream of DKK1 and underlying mechanism.
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| Contributor(s) |
Sui Q, Liu D, Han K, Liu G, Jiang W, Liao L, Tang J, Li Y, Kong L, Ou Q, Xiao B, Ling Y, Chen J, Liu Z, Zuo Z, Pan Z, Zheng J, Cai M, Zhou P, Ding P |
| Citation(s) |
33782107 |
| Submission date |
Apr 23, 2020 |
| Last update date |
Apr 07, 2021 |
| Contact name |
Qiaoqi Sui |
| E-mail(s) |
suiqq@sysucc.org.cn
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| Phone |
+8613602473301
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| Organization name |
Sun Yat-sen University Cancer Center
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| Street address |
Dongfeng East Road 651
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| City |
Guangzhou |
| ZIP/Postal code |
510060 |
| Country |
China |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA627657 |
| SRA |
SRP258101 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE149206_processed_data_files.txt.gz |
4.4 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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