Dickkopf 1 Impairs Sensitivity to PD-1 Blockade through CD8+ T Cell Inactivation in dMMR/MSI Colorectal Cancer
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ABSTRACT:
PROVIDER: PRJNA627657 | ENA |
REPOSITORIES: ENA
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Project description: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.
2021-04-07 | GSE149206 | GEO
Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.
2008-12-18 | GSE13911 | GEO
Project description:Colorectal cancer, one of the most frequent types of malignancy in the Western world, develops through a multi-step process. The main pathways establishing transformation of normal mucosa to invasive carcinoma include chromosomal instability (CIN), microsatellite instability (MSI) or epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological and genetic characteristics. In general, altered cell surface glycosylation has been linked to colorectal cancer progression, however the impact of MSI-specific pathways on the glycosylation machinery of MSI colon cancer cells has not been investigated yet. In a recent study (Patsos et al., 2009) we have shown that MSI-specific mutations induce marked alterations in cell surface glycosylation, indicating specific changes in the expression of glyco-genes. Therefore the purpose of our experiment is to define these changes by glyco-gene chip analysis. Biallelic mutational inactivation of MSI target genes is believed to drive MSI tumorigenesis. TGFBR2, ACVR2 and AIM2 are among the most frequently mutated genes in MSI colorectal adenomas and carcinomas and functional studies indicate their contribution to MSI-carcinogenesis. A first general screening approach by lectin FACS analysis indicated a correlation between functional inactivation of these genes and cell surface glycosylation of the MSI colon cell line HCT116 (Patsos et al., 2009). For detailed analysis of the altered glycosylation pattern and the underlying molecular mechanisms we have established HCT116 double stable transfectants that allow doxycycline-inducible expression of the three MSI target genes TGFBR2, ACVR2 and AIM2 in a reversible manner. Thus we can experimentally control the expression of the MSI-genes and analyze short and long-term effects on different cell functions, including glycosylation. From the application of the glyco-gene chip for analysis of the transfectants we expect to gain seminal information on the influence of MSI-target genes on glycan expression and function in MSI tumor cells. Correlating loss-of-function of MSI target genes not yet linked with glycosylation to the regulation of the glycophenotype is a novel approach to investigate the glycobiology of tumor cells. In addition it is also suitable to detect new MSI-(glyco)markers for clinical applications, including diagnostic tumor markers and specific targets for immunotherapies.
2011-09-05 | E-GEOD-31927 | biostudies-arrayexpress
Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response. Experiment Overall Design: Genes differentially expressed between MSI and MSS tumours were identified as follows: (i) gene probe sets were pre-selected for being flagged as ‘PRESENT’ in at least 10 tumour samples (21,324 probe sets); (ii) the probe set signal values on the pre-selected probe sets were used to run a t-test between the two types of tumour samples; (iii) the false discovery rate (FDR) method was applied to the t-test calculated p-values to correct for multiple testing and (iv) a false discovery rate <0.05 and a t-test p-value < 0.01 were chosen as threshold criteria to identify the genes differentially expressed in tumours with and without MSI
2009-01-03 | E-GEOD-13911 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8802534 | biostudies-literature
Project description:KEYNOTE-177 is currently the only randomized controlled phase III clinical trial evaluating the efficacy and safety of pembrolizumab versus standard chemotherapy combined with targeted first-line therapy for dMMR/MSI-H metastatic colorectal cancer. The study was conducted at 192 centers in 23 countries and enrolled a total of 307 subjects. The results of the study showed that the median PFS of pembrolizumab was 16.5 months, which was double the 8.2 months in the chemotherapy group (HR 0.60; 95% CI: 0.45-0.80; P = 0.0002). In addition, the ORR was 45.1% in the pembrolizumab group and 33.1% in the chemotherapy group, and a higher percentage of patients achieving a complete remission (CR) with pembrolizumab than in the chemotherapy group (13.1% vs. 3.9%). The U.S. FDA approved pembrolizumab in June 2020 for the first-line treatment of MSI-H/dMMR metastatic colorectal cancer.
The results of the KEYNOTE-177 study showed that 29% of patients with dMMR/MSI-H metastatic colorectal cancer experienced direct disease progression (PD) after first-line pembrolizumab monotherapy. This may suggest that some dMMR/MSI-H patients have primary resistance to anti-PD-1 monotherapy. In the first-line treatment cohort of the CheckMate 142 study using nivolumab combined with ipilimumab, the proportion of patients with direct PD was 13%, suggesting that the combination of PD-1 inhibitors and anti-CTLA-4 mAb may have help overcome this primary resistance. In addition, in the second-line and above cohort of the CheckMate142 study, 12% of patients receiving nivolumab in combination with ipilimumab experienced PD directly, compared with 26% of patients receiving nivolumab alone.
A study published on 《The Lancet Oncolog》 on the efficacy and safety of ipilimumab monotherapy and ipilimumab combined with anti-PD-1 monoclonal antibody in patients with anti-PD-1 monoclonal antibody-resistant melanoma Retrospective study. The study included 355 patients with unresectable metastatic stage III or IV melanoma who received ipilimumab monotherapy after failure of anti-PD-(L)1 monoclonal antibody (n=162), or Ipilimumab combined with anti-PD-1 therapy (n=193). The ORR was 31% in the combination arm, significantly higher than the 13% in the ipilimumab monotherapy arm. In addition, the median OS and PFS of the combination therapy group were 20.4 months and 3.0 months, respectively, which were also significantly higher than those of the single-agent group of 8.8 months and 2.6 months.
The aim of this study was to evaluate the objective response rate (ORR) of Cadonilimab, a bispecific anti-PD-1/CTLA-4 antibody, for PD-1/PD-L1 blockade-refractory, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), advanced colorectal cancer.
| 2736356 | ecrin-mdr-crc
Project description:Inhibition of the nonsense mediated decay (NMD) mechanism in cells results in stabilization of transcripts carrying premature translation termination codons. A strategy referred to as gene indentification by NMD inhibition (GINI) has been proposed to identify genes carrying nonsense mutations (Noensie & Dietz, 2001). Genes containing frameshift mutations in colon cancer cell line have been identifying mutatnt genes using GINI, we have now further improved the strategy. In this approach, inhibition of NMD with emetine is complemented with inhibiting NMD by blocking the phosphorylation of the hUpf1 protein with caffeine. In addition, to enhance the GINI strategy, comparing mRNA level alterations produced by inhibiting transcription alone or inhbiiting transcription together with NMD following caffeine pretreatment were used for the efficient identification of false positives produced as a result of stress response to NMD inhibition. To demonstrate the improved efficiency of this approach, we analyzed colon cancer cell lines showing microstellite instability. Bi-allelic inactivating mutations were found in the FXR1, SEC1L1, NCOR1, BAT3, PHD14, ZNF294, C190ORF5 genes as well as genes coding for proteins with yet unknown functions. Experiment Overall Design: Using GINI2 as a method of identifying novel biallelic truncating mutations in MSI+ colon cancer cells, various treatment conditions were applied to cultured colon cancer cell lines LS180 (MSI+) and SW480 (MSI-) and gene expression profiling was measured using Affymetrix GeneChip U133 Plus 2 arrays.
2008-06-13 | E-GEOD-5486 | biostudies-arrayexpress
Project description:Microsatellite instability (MSI), caused by defective mismatch repair, is observed in a subset of colorectal cancers (CRCs). We evaluated somatic mutations in microsatellite repeats of genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat. Expression profiling of 34 MSI colorectal cancers and 15 normal colonic mucosas was performed in 2002. Comparison of malignant and healthy tissue.
2011-03-01 | E-GEOD-24514 | biostudies-arrayexpress