Cancer Cell
Volume 39, Issue 5, 10 May 2021, Pages 662-677.e6
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Article
Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy

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Highlights

  • Single-cell RNA-seq reveals the architecture of the ccRCC immune microenvironment

  • Multiregional immune phenotypes integrated with bulk RNA-seq and tumor pathology

  • TCR usage varies by phenotype and defines T cell differentiation trajectories

  • Signatures of tissue-resident T cells and TAMs predict clinical outcome

Summary

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

Keywords

renal cell carcinoma
single-cell RNA-sequencing
TCR sequencing
immunotherapy
tyrosine kinase inhibitors
tissue-resident
tumor-associated macrophages
pathology

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