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

Sharon L Freshour; Timothy H-P Chen; Bryan Fisk; Haolin Shen; Matthew Mosior; Zachary L Skidmore; Catrina Fronick; Jennifer K Bolzenius; Obi L Griffith; Vivek K Arora; Malachi Griffith

doi:10.1016/j.isci.2023.107937

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

iScience. 2023 Sep 15;26(10):107937. doi: 10.1016/j.isci.2023.107937. eCollection 2023 Oct 20.

Authors

Sharon L Freshour¹, Timothy H-P Chen¹, Bryan Fisk^{1

2}, Haolin Shen¹, Matthew Mosior^{1

2}, Zachary L Skidmore^{1

2}, Catrina Fronick², Jennifer K Bolzenius^{1

3}, Obi L Griffith^{1

2

3

4}, Vivek K Arora^{1

3}, Malachi Griffith^{1

2

3

4}

Affiliations

¹ Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
² McDonnell Genome Institute, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
³ Siteman Cancer Center, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
⁴ Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.

Abstract

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.

Keywords: Immunology; Oncology; Transcriptomics.

Abstract

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