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Series GSE149206 Query DataSets for GSE149206
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
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.
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.
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
Phone +8613602473301
Organization name Sun Yat-sen University Cancer Center
Street address Dongfeng East Road 651
City Guangzhou
ZIP/Postal code 510060
Country China
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (22)
GSM4492232 C1 RNA-seq
GSM4492233 C2 RNA-seq
GSM4492234 C3 RNA-seq
BioProject PRJNA627657
SRA SRP258101

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Supplementary file Size Download File type/resource
GSE149206_processed_data_files.txt.gz 4.4 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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