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Immunosuppressive crosstalk between tumour cells, myeloid cells and T cells in an anti-PD-1 plus anti-CTLA-4 therapy resistant mouse ccRCC model [RNA-seq]

ABSTRACT: Many patients respond poorly or develop resistance to immune checkpoint therapies for metastatic clear cell renal cell carcinoma (ccRCC). Here we demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant autochthonous mouse model are resistant to anti-PD-1 plus anti-CTLA-4 therapy, providing a model of checkpoint therapy resistance. In vivo checkpoint therapy allowed isolated T cells to recognise cultured ccRCC cells, implicating the tumour microenvironment in suppression of T cell activation. Single cell RNA-seq identified putative immunosuppressive PMN-MDSC, M-MDSC and TAM populations that show similar features to myeloid cells in the microenvironment of human ccRCC. Conditioned medium of ccRCC cell lines attracted bone marrow-derived macrophages in a MIF-dependent manner and induced the mis-differentiation of bone marrow cells to M-MDSC and TAM2-like phenotypes. These cells suppressed the viability and proliferation of activated CD8+ T cells. These analyses identify new candidate cellular and molecular barriers to effective immune checkpoint therapy. We validate this concept by showing that GALECTIN-3 is the predominant checkpoint ligand expressed by ccRCC cells and myeloid cells and that anti-LAG-3 treatment increases T cell infiltration in this model.

ORGANISM(S): Mus musculus

PROVIDER: GSE259359 | GEO | 2025/02/27

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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Immunosuppressive crosstalk between tumour cells, myeloid cells and T cells in an anti-PD-1 plus anti-CTLA-4 therapy resistant mouse ccRCC model [RNA-seq]

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