Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy

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)-naive 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.

Automated summary

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, and this study investigates the immune landscape of ccRCC using paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing, revealing extensive heterogeneity within and between patients. The study shows that tissue-resident T cells and tumor-associated macrophages (TAMs) are associated with responses to immune checkpoint blockade (ICB) and targeted therapies, highlighting the importance of cellular programs in therapeutic efficacy for ccRCC.