Whereas initial studies focused on the role of anti-PD-1/PD-L1 in reversing in situ terminal exhaustion of CD8 T cells, data obtained from preclinical tumor models and studies in cancer patients showed that responsiveness was dependent upon both reversal of exhaustion at the tumor site and proliferation of early exhausted peripheral CD8 T cells [4,24]. The gene discussed is CD8A; the disease is cancer.