Distinct Chromatin States Underlie Tumor-Specific T-cell Dysfunction

PD-1/PDL-1 blockade harnesses tumor-specific CD8⁺ T cells to achieve clinical responses in a variety of tumors. However, some patients fail to respond to checkpoint blockade, and solid tumors can progress despite the presence of tumor-specific CD8⁺ T cells, suggesting the T cells are dysfunctional. Philip and colleagues hypothesized that T-cell dysfunction may be epigenetically imprinted, and used the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to assess genome-wide chromatin accessibility changes during T-cell differentiation in a mouse model of hepatocellular carcinoma. Tumor-specific T cells exhibited a distinct epigenetic trajectory compared with T cells after acute infection. Massive chromatin remodeling occurred by day 5 following tumor induction, with a second wave of remodeling between days 7 and 14; little remodeling occurred after the second wave. These findings suggest that tumor-specific T cells differentiate through two chromatin states: an early dysfunctional state 1 and a later persistent dysfunctional state 2. State 1 dysfunction was plastic and reversible, but further chromatin remodeling induced a fixed state 2 dysfunction. State 1 T cells exhibited low expression of CD38, CD101, and CD30L, and high expression of CD5 compared with state 2 T cells, but both the state 1 and 2 cells expressed similar levels of the inhibitory receptors PD1 and LAG3. Dysfunctional T cells that could be functionally rescued lacked CD38 and CD101. Memory T cells in a “functionally poised” state underwent rapid chromatin remodeling in tumors to become state 2 fixed dysfunctional tumor-specific T cells. ATAC-seq showed that tumor-infiltrating PD1^hi CD8⁺ T cells from human melanoma and non–small cell lung tumors had similar chromatin accessibility states as dysfunctional state 2 tumor-specific T cells, but a subset displayed higher levels of CD38 and CD101, and lower levels of CD5. In addition to defining the chromatin states that underlie T-cell dysfunction, these findings suggest that CD38, CD101, and other cell surface proteins may be potential biomarkers to predict immunotherapy efficacy.

Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 2017;545:452–6.