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ScRNA-seq of cancer and CD8+ cells during early metastasis identifies targetable subpopulations and immune evasion mechanisms

ABSTRACT: Profiling tumors at single-cell resolution provides an opportunity to understand complexities underpinning lymph-node metastases in head and neck squamous-cell carcinoma. Single-cell RNAseq (scRNAseq) analysis of cancer-cell trajectories identified a sub-population of pre-metastatic cells, driven by actionable pathways including AXL and AURK. Blocking these two proteins blunted tumor invasion in patient-derived cultures. Furthermore, scRNAseq analyses of tumor-infiltrating CD8+ T-lymphocytes showed two distinct trajectories to T-cell dysfunction, corroborated by their clonal architecture based on single-cell T-cell receptor sequencing. By determining key modulators of these trajectories, followed by validation using external datasets and functional experiments, we uncovered a novel role for SOX4 in mediating T-cell exhaustion. Finally, interactome-analyses between pre-metastatic tumor-cells and CD8+ T-lymphocytes uncovered a putative role for the Midkine pathway in immune-modulation; this was confirmed by scRNAseq of tumors from humanized mice. Aside from specific findings, this study demonstrates the importance of tumor heterogeneity analyses in identifying key vulnerabilities during early metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188737 | GEO | 2023/02/17

REPOSITORIES: GEO

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scRNA-seq of cancer and CD8+ cells during early metastasis identifies targetable subpopulations and immune evasion mechanisms

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