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Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer
To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4(+) T cell depl...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558731/ https://www.ncbi.nlm.nih.gov/pubmed/37810214 http://dx.doi.org/10.1016/j.isci.2023.107937 |
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author | Freshour, Sharon L. Chen, Timothy H.-P. Fisk, Bryan Shen, Haolin Mosior, Matthew Skidmore, Zachary L. Fronick, Catrina Bolzenius, Jennifer K. Griffith, Obi L. Arora, Vivek K. Griffith, Malachi |
author_facet | Freshour, Sharon L. Chen, Timothy H.-P. Fisk, Bryan Shen, Haolin Mosior, Matthew Skidmore, Zachary L. Fronick, Catrina Bolzenius, Jennifer K. Griffith, Obi L. Arora, Vivek K. Griffith, Malachi |
author_sort | Freshour, Sharon L. |
collection | PubMed |
description | To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4(+) T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4(+) T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity. |
format | Online Article Text |
id | pubmed-10558731 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-105587312023-10-08 Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer Freshour, Sharon L. Chen, Timothy H.-P. Fisk, Bryan Shen, Haolin Mosior, Matthew Skidmore, Zachary L. Fronick, Catrina Bolzenius, Jennifer K. Griffith, Obi L. Arora, Vivek K. Griffith, Malachi iScience Article To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4(+) T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4(+) T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity. Elsevier 2023-09-15 /pmc/articles/PMC10558731/ /pubmed/37810214 http://dx.doi.org/10.1016/j.isci.2023.107937 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Freshour, Sharon L. Chen, Timothy H.-P. Fisk, Bryan Shen, Haolin Mosior, Matthew Skidmore, Zachary L. Fronick, Catrina Bolzenius, Jennifer K. Griffith, Obi L. Arora, Vivek K. Griffith, Malachi Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title | Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title_full | Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title_fullStr | Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title_full_unstemmed | Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title_short | Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer |
title_sort | endothelial cells are a key target of ifn-g during response to combined pd-1/ctla-4 icb treatment in a mouse model of bladder cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558731/ https://www.ncbi.nlm.nih.gov/pubmed/37810214 http://dx.doi.org/10.1016/j.isci.2023.107937 |
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