However, chronic antigen exposure in cancer leads to CD8+ T cell exhaustion with upregulation of markers including PD-1, Tim3 as well as epigenetic changes.1–3 Blockade of PD-1 promotes CD8+ T cell expansion and reinvigoration leading to robust clinical responses in many different types of cancer.4–7 Interestingly, CD8+ PD-1+ T cells within the tumor microenvironment are heterogenous with subsets including progenitor stem-like CD8+ T cell and terminally differentiated effector like cells (TE).8,9 The stem-like subset, in contrast to the TE, expresses the transcription factor Tcf-1. The gene discussed is CD8A; the disease is cancer.