Stayin’ Alive: Targeting chromatin regulators of clonal hematopoiesis promotes CD8 T cell stemness

Abstract T cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T cell population (Tpex) is correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues find three epigenetic regulators commonly mutated in clonal hematopoiesis also control Tpex progression to exhaustion. By leveraging the finding that patients with enhanced survival in myelodysplastic syndrome (MDS) had T cell mutations in the ASXL1 gene, this study demonstrates that loss of ASXL1 in T cells preserves their stem-cell like properties of self-renewal and survival leading to increased anti-tumor responses when combined with immunotherapy in both mouse models and human cancers. These findings have significant implications for new therapeutic options that target epigenetic modifiers promoting exhaustion together with immune checkpoint blockade to improve response rates in patients.