Using scATACseq to probe the landscape of infiltrating T cells in RCC (a tumor where high T cell infiltration associates with poor survival), Kourtis, Wang, and Wang et al. demonstrated that the chromatin landscape could be used to infer T cell states and the transcription factors that form the underlying dynamic regulatory networks. Single-cell transcriptome analysis was concordant. Unexpectedly, NF-κB and its downstream targets were revealed as a key pathway associated with late dysfunction, driving T cells toward an apoptotic state. An apoptotic signature inversely correlated with patient survival (TCGA) and response to anti-PD-1 therapy.
Contributed by Ed Fritsch
ABSTRACT: 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 guide therapeutic strategies. Here, we map the single-cell chromatin landscape of immune cells from blood, normal tumor-adjacent kidney tissue and malignant tissue from patients with early-stage clear cell renal cell carcinoma (ccRCC). We catalog the T cell states dictated by tissue-specific and developmental-stage-specific chromatin accessibility patterns, infer key chromatin regulators and observe rewiring of regulatory networks in the progression to dysfunction in CD8+ T cells. Unexpectedly, among the transcription factors orchestrating the path to dysfunction, NF-κB is associated with a pro-apoptotic program in late stages of dysfunction in tumor-infiltrating CD8+ T cells. Importantly, this epigenomic profiling stratified ccRCC patients based on a NF-κB-driven pro-apoptotic signature. This study provides a rich resource for understanding the functional states and regulatory dynamics of immune cells in ccRCC.