3D genome of CD8+ T cells reveals IRF8-mediated exhaustion in cancer

CD8+ T cell responses are essential for anti-tumor immunity, but chronic antigen exposure in cancer can lead to T cell exhaustion, marked by high PD-1 expression. Recent studies have identified progenitor-like CD8+ T cells (Tprog cells) within tumor-infiltrating lymphocytes (TILs) that sustain antitumor responses. These cells can differentiate into terminally exhausted cells (Tterm cells), losing their proliferative and effector functions. Immunotherapy aims to enhance CD8+ TILs functionality, promoting their transition from Tprog to Tterm cells. However, the mechanisms behind this exhaustion remain unclear. Single-cell RNA sequencing and ATAC-seq have revealed distinct profiles and chromatin accessibility between progenitor and terminally exhausted states. Histone modifications predict a loss of enhancer-promoter contacts during this transition. Chromatin structure plays a crucial role in T cell differentiation. We constructed a high-resolution 3D genome map of CD8+ T cell subsets and, through multi-omics integration, identified chromatin structure changes linked to T cell exhaustion, including alterations in topologically associating domains (TADs) and chromatin loops, providing new insights into the genetic basis of CD8+ T cell exhaustion in cancer. Overall design: Hi-C experiment of naïve, effector,memory, progenitor exhausted, terminal exhausted CD8 T cells in E.G7 tumor and LCMV clone 13 models. Hi-C for cotransferred WT and Irf8-/- OT-I TILs from E.G7 tumors