Tumor-infiltrating lymphocytes (TILs) can become functionally disabled within the tumor environment. In Nature, Schietinger and colleagues assess the epigenetic changes that manifest after inactivation of TILs. Through the use of an inducible liver-cancer model and infusion of tumor-specific CD8+ T cells, they identify two waves of chromatin remodeling that occur in the TILs between day 5 and day 7 (stage 1) and after day 14 (stage 2). These chromatin changes include increased accessibility of sites recognized by the transcription factor NFATc1 and decreased accessibility of sites recognized by TCF1, which leads to the concordant upregulation of inhibitory molecules such as CTLA-4, PD-1 and LAG3 and downregulation of the effector molecules TNF and IFN-γ. This epigenetic reprogramming is reversible in cells at stage 1 but becomes a fixed dysfunctional state in cells at stage 2, and these states can be phenotypically distinguished by the expression of CD5, CD38 and CD101. Human CD8+ TILs can also be distinguished phenotypically and epigenetically by those markers, which might be used as surrogates to determine patients' responses to immunotherapy. LAD

Nature (17 May 2017) doi:10.1038/nature22367