CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia
Caitlin C. Zebley, Charmaine Brown, Mi Tian, Yiping Fan, Shanta Alli, Shannon K. Boi, Giovanni Galletti, Enrico Lugli, Deanna Langfitt, Jean‐Yves Métais, Timothy Lockey, Michael M. Meagher, Brandon M. Triplett, Aimee C. Talleur, Stephen Gottschalk, Ben Youngblood
Abstract
CD19-CAR T cells post-infusion in ALL patients. We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes. The CAR T cell post-infusion changes are further characterized by repression of genes (e.g., TCF7 and LEF1) associated with memory potential and a DNA methylation signature (e.g., demethylation at CX3CR1, BATF, and TOX) demarcating a transition toward exhaustion-progenitor T cells. Thus, CD19-CAR T cells undergo exhaustion-associated DNA methylation programming, indicating that efforts to prevent this process may be an attractive approach to improve CAR T cell efficacy.