Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling
Aim: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and is characterized by T-cell exhaustion, particularly in effector CD8+ T-cells. This exhaustion, driven by persistent immunosuppressive signals in the tumor microenvironment, impairs immune function and hin...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Open Exploration Publishing Inc.
2025-01-01
|
| Series: | Exploration of Immunology |
| Subjects: | |
| Online Access: | https://www.explorationpub.com/uploads/Article/A1003179/1003179.pdf |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832586132851785728 |
|---|---|
| author | Rawaa AlChalabi Raghda Makia Semaa A. Shaban Ahmed AbdulJabbar Suleiman |
| author_facet | Rawaa AlChalabi Raghda Makia Semaa A. Shaban Ahmed AbdulJabbar Suleiman |
| author_sort | Rawaa AlChalabi |
| collection | DOAJ |
| description | Aim: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and is characterized by T-cell exhaustion, particularly in effector CD8+ T-cells. This exhaustion, driven by persistent immunosuppressive signals in the tumor microenvironment, impairs immune function and hinders effective immunotherapy. This study aimed to identify key exhaustion-related marker genes in CD8+ T-cells linked to PDAC and assess the potential of repurposing anti-inflammatory drugs to counteract T-cell exhaustion and enhance immune responses against PDAC. Methods: We employed a multi-omics approach, integrating single-cell RNA sequencing data with whole genome sequencing to identify dysregulated exhaustion-related immune markers in CD8+ T-cells in PDAC. We examined gene expression profiles and conducted functional enrichment analysis to evaluate their roles in immune exhaustion. We analyzed mutations in the shortlisted biomarkers from The Cancer Genome Atlas (TCGA) and performed in silico mutational analysis using Maestro to evaluate the impact of an IL7R mutation (K110N) on protein function. Virtual screening using a deep learning framework, GNINA, explored the inhibitory features of the anti-inflammatory drugs oxaprozin and celecoxib on IL7R. Results: Key dysregulated exhaustion-related immune markers were identified including PRF1, GZMA, CD8A, CD3D, NKG7, IL7R, and IL2RG. Pathway enrichment analysis indicated significant involvement in T-cell receptor signaling, Th1 and Th2 differentiation, and Th17 differentiation pathways, correlating with reported poor survival outcomes in PDAC patients. Mutational analysis of IL7R revealed a likely pathogenic mutation (K110N) located in the IL-7Ralpha fibronectin type III domain. Drug repurposing of oxaprozin and celecoxib showed favorable binding interactions with both wild and mutant IL7R proteins. Conclusions: The K110N mutation, despite not causing significant structural changes, may impact T-cell and B-cell homeostasis and development. Our findings suggest that oxaprozin and celecoxib could effectively inhibit T-cell exhaustion through favorable interactions with IL7R. Further clinical studies are necessary to validate the therapeutic potential of these anti-inflammatory drugs in enhancing immune responses in pancreatic cancer. |
| format | Article |
| id | doaj-art-70c8b48dd8c34251bc83412d329b2cbf |
| institution | Kabale University |
| issn | 2768-6655 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Open Exploration Publishing Inc. |
| record_format | Article |
| series | Exploration of Immunology |
| spelling | doaj-art-70c8b48dd8c34251bc83412d329b2cbf2025-01-26T08:36:44ZengOpen Exploration Publishing Inc.Exploration of Immunology2768-66552025-01-015100317910.37349/ei.2025.1003179Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profilingRawaa AlChalabi0https://orcid.org/0000-0002-1570-2537Raghda Makia1https://orcid.org/0000-0002-1490-7469Semaa A. Shaban2https://orcid.org/0000-0002-0538-8716Ahmed AbdulJabbar Suleiman3https://orcid.org/0000-0001-7427-4483Department of Molecular and Medical Biotechnology, College of Biotechnology, Al-Nahrain University, Baghdad 10070, IraqDepartment of Plant Biotechnology, College of Biotechnology, Al-Nahrain University, Baghdad 10070, IraqDepartment of Biology, College of Science, Tikrit University, Tikrit 34001, IraqDepartment of Biotechnology, College of Science, University of Anbar, Ramadi 31001, IraqAim: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and is characterized by T-cell exhaustion, particularly in effector CD8+ T-cells. This exhaustion, driven by persistent immunosuppressive signals in the tumor microenvironment, impairs immune function and hinders effective immunotherapy. This study aimed to identify key exhaustion-related marker genes in CD8+ T-cells linked to PDAC and assess the potential of repurposing anti-inflammatory drugs to counteract T-cell exhaustion and enhance immune responses against PDAC. Methods: We employed a multi-omics approach, integrating single-cell RNA sequencing data with whole genome sequencing to identify dysregulated exhaustion-related immune markers in CD8+ T-cells in PDAC. We examined gene expression profiles and conducted functional enrichment analysis to evaluate their roles in immune exhaustion. We analyzed mutations in the shortlisted biomarkers from The Cancer Genome Atlas (TCGA) and performed in silico mutational analysis using Maestro to evaluate the impact of an IL7R mutation (K110N) on protein function. Virtual screening using a deep learning framework, GNINA, explored the inhibitory features of the anti-inflammatory drugs oxaprozin and celecoxib on IL7R. Results: Key dysregulated exhaustion-related immune markers were identified including PRF1, GZMA, CD8A, CD3D, NKG7, IL7R, and IL2RG. Pathway enrichment analysis indicated significant involvement in T-cell receptor signaling, Th1 and Th2 differentiation, and Th17 differentiation pathways, correlating with reported poor survival outcomes in PDAC patients. Mutational analysis of IL7R revealed a likely pathogenic mutation (K110N) located in the IL-7Ralpha fibronectin type III domain. Drug repurposing of oxaprozin and celecoxib showed favorable binding interactions with both wild and mutant IL7R proteins. Conclusions: The K110N mutation, despite not causing significant structural changes, may impact T-cell and B-cell homeostasis and development. Our findings suggest that oxaprozin and celecoxib could effectively inhibit T-cell exhaustion through favorable interactions with IL7R. Further clinical studies are necessary to validate the therapeutic potential of these anti-inflammatory drugs in enhancing immune responses in pancreatic cancer.https://www.explorationpub.com/uploads/Article/A1003179/1003179.pdfpancreatic ductal adenocarcinomaeffector cd8+ t-cellsimmunosuppressionexhaustive immune biomarkersanti-inflammatory drugs |
| spellingShingle | Rawaa AlChalabi Raghda Makia Semaa A. Shaban Ahmed AbdulJabbar Suleiman Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling Exploration of Immunology pancreatic ductal adenocarcinoma effector cd8+ t-cells immunosuppression exhaustive immune biomarkers anti-inflammatory drugs |
| title | Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling |
| title_full | Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling |
| title_fullStr | Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling |
| title_full_unstemmed | Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling |
| title_short | Characterizing immune biomarkers and effector CD8+ T-cell exhaustion in pancreatic adenocarcinoma via single-cell RNA sequencing profiling |
| title_sort | characterizing immune biomarkers and effector cd8 t cell exhaustion in pancreatic adenocarcinoma via single cell rna sequencing profiling |
| topic | pancreatic ductal adenocarcinoma effector cd8+ t-cells immunosuppression exhaustive immune biomarkers anti-inflammatory drugs |
| url | https://www.explorationpub.com/uploads/Article/A1003179/1003179.pdf |
| work_keys_str_mv | AT rawaaalchalabi characterizingimmunebiomarkersandeffectorcd8tcellexhaustioninpancreaticadenocarcinomaviasinglecellrnasequencingprofiling AT raghdamakia characterizingimmunebiomarkersandeffectorcd8tcellexhaustioninpancreaticadenocarcinomaviasinglecellrnasequencingprofiling AT semaaashaban characterizingimmunebiomarkersandeffectorcd8tcellexhaustioninpancreaticadenocarcinomaviasinglecellrnasequencingprofiling AT ahmedabduljabbarsuleiman characterizingimmunebiomarkersandeffectorcd8tcellexhaustioninpancreaticadenocarcinomaviasinglecellrnasequencingprofiling |