A single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma (scRNA-Seq and TCR-Seq)

A complete chart of the chromatin regulatory elements of immune cells in patients with cancer and their dynamic behavior is necessary to understand the developmental fates and to guide therapeutic strategies. Here, we map, at the single-cell level, the chromatin landscape of immune cells from blood, normal adjacent kidney, and malignant tissue from patients with early-stage clear cell renal cell carcinoma (ccRCC). Specifically in T cells, we catalogue the various cell states dictated by tissue- and developmental stage-specific chromatin accessibility patterns and we infer key chromatin regulators of these states. In the CD8+ T cells progression to dysfunction, we observe an extensive rewiring of the regulatory networks. Unexpectedly, we find that among the transcription factors that orchestrate the path to dysfunction, NFkB, a transcription factor with an established prosurvival role during TCR-mediated activation, is associated with a proapoptotic program in late stages of dysfunction in ccRCC infiltrating CD8+ T cells. Importantly, the epigenomic profiling can stratify RCC patients based on a NFkB-driven proapoptotic signature which was also validated at the gene expression and protein level. Our study provides a rich resource for understanding the functional states and regulatory dynamics of immune cells in RCC. Overall design: We used single cell RNA-seq (5' RNA expression sequencing) and TCR-sequencing (VDJ sequencing) of human immune cells from blood, normal adjacent kidney, and malignant tissues from early stage clear cell renal cell carcinoma patients at baseline. The VDJ region sequencing is included in the 5' RNA expression sequencing as in 10x Genomics Chromium protocols