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Single Cell RNA sequencing of mouse SQ tumor from C57BL/6 with or with liver tumor.

ABSTRACT: The presence of liver tumor changes the transcriptome of SQ tumor-infiltrating adaptive and innate immune cells. We report differential transcriptomic changes within in the SQ tumor immune infiltrate of mice with and without concurrent liver tumor implantation within their livers. We show heatmap displaying the top 20 differentially expressed genes by SQ MDSC and Tregs between the two groups via scRNAseq. Violin plots showing the top 2 differentially upregulated genes by SQ Tregs from mice with liver tumor. Heatmap displaying the top 20 differentially upregulated genes by SQ CD8 T cells between the two groups. Violin plots showing differential expression of ICOS and CTLA-4 by SQ CD8 T cells between the two groups. Unbiased re clustering (UMAP) and stacked bar graph of relative frequencies of monocyte/myeloid cells showing 9 distinct scRNAseq subclusters. Violin plots showing relative MDSC score ordered by monocyte/myeloid cell subclusters. Our data suggests that mice with liver tumors have increased activation of Tregs, decreased activation of CD8 T cells and transcriptomic modifications within the MDSC compartment within their SQ tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE157653 | GEO | 2020/09/09

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cell (MDSC) levels are elevated in cancer patients and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton’s Tyrosine Kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the anti-tumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of FACS-enriched MDSC from patients with different cancer types (breast, melanoma, head and neck squamous cell cancer - HNSCC). Melanoma patient MDSC were treated in vitro for 4h with 5 µM ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10x Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from breast and HNSCC cancer patients revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from melanoma patients resulted in significant changes in gene expression. GBP1, IL 1β and CXCL8 were among the top downregulated genes while RGS2 and ABHD5 were among the top upregulated genes (p<0.001). double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes when compared to early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL 6 signaling (p<0.004). ScRNA-seq revealed characteristic gene expression patterns for MDSC from different cancer patients. BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration. Myeloid-derived suppressor cell (MDSC) levels are elevated in cancer patients and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton’s Tyrosine Kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the anti-tumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of FACS-enriched MDSC from patients with different cancer types (breast, melanoma, head and neck squamous cell cancer - HNSCC). Melanoma patient MDSC were treated in vitro for 4h with 5 µM ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10x Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from breast and HNSCC cancer patients revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from melanoma patients resulted in significant changes in gene expression. GBP1, IL 1β and CXCL8 were among the top downregulated genes while RGS2 and ABHD5 were among the top upregulated genes (p<0.001). double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes when compared to early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL 6 signaling (p<0.004). ScRNA-seq revealed characteristic gene expression patterns for MDSC from different cancer patients. BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

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Single Cell RNA sequencing of mouse SQ tumor from C57BL/6 with or with liver tumor.

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