增强子驱动的基因调控网络揭示调控肿瘤微环境中 T 细胞适应与分化的转录因子

Tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory CD8 + T cell (Trm) phenotype are associated with improved patient outcomes in solid malignancies. To define programs governing the formation of Trm-like TIL, we performed paired single-cell RNA sequencing and single-cell ATAC sequencing of T cell receptor (TCR)-matched CD8 + T cells in models of infection and cancer. Enhancer-driven regulons assembled from multiomic profiling data revealed epigenetic and transcriptional programs regulating the formation of Trm-like TIL in relation to canonical exhausted and memory T cell states.

The transcriptional regulator KLF2 repressed the formation of CD69 + CD103 + Trm-like TIL and limited anti-tumor activity. Conversely, sustained expression of the transcription factor BATF enhanced formation of CD69 + CD103 + TIL, contingent upon downregulation of KLF2. Transforming growth factor (TGF- ) signaling and CD103 expression were necessary for Trm-like TIL formation, but BATF overexpression was sufficient to drive formation of CD69 + CD103 + TIL in TGFBR2-silenced cells.

These findings reveal mechanisms of Trm-like TIL differentiation and provide a framework for considering tissue residency in the context of CD8 + T cell heterogeneity in the tumor microenvironment.