LN-stem, tumor stem, tumor terminally differentiated CD8 T cells from human kidney cancer

This work aimed to understand the source of TCF1+ CD8 T cells in tumors. By studying human tumor draining lymph-nodes (TDLNs), we find that CD8 T cells activate in TDLN but fail to acquire the normal effector program. Instead, these CD8 T cells share functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. This suggests that these activated cells are a precursor to the stem-like CD8 T cells in tumors. By using mouse models, we show that tumor-specific CD8 T cells are activated in TDLN, but do not acquire an effector phenotype. These cells then migrate into the tumor where they require additional co-stimulation from antigen presenting cells to acquire the effector program. This is strikingly different from canonical CD8 T cell activation to acute viruses, where the effector program is acquired immediately. This model of T cell differentiation has important implications to improve immunotherapy. Overall design: CD8 T cell populations were sorted from human PBMCs, lymph nodes, and tumor. RNA was extracted using qiagen micro all-prep columns. RNA was sequenced on an Illumina Hiseq 3000 Cell sorting was performed byFACS Aria II (BD Biosciences). For scRNA-seq (10x) of mouse samples live, CD3-CD19-Ly6G+ I-A/I-E+ cells were sorted from naïve LN, tumor-draining LN, and TRAMPC1-GP tumors. For human scRNA-seq (10x) fresh kidney tumors were used, antigen-presenting cells were sorted as live, CD45+, CD3-, HLADR+