TET2 guards against unchecked BATF3-induced CAR T cell expansion
Nayan Jain, Zeguo Zhao, Judith Feucht, Richard P. Koche, Archana Iyer, Anton Dobrin, Jorge Mansilla‐Soto, Julie L. Yang, Yingqian A. Zhan, Michael Lopez, Gertrude Gunset, Michel Sadelain
Abstract
Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies1–5. As T cell differentiation and functional states are associated with distinct epigenetic profiles6,7, we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten–eleven translocation 2 (TET2)8 presents an interesting opportunity as its loss may enhance T cell memory9,10, albeit not cause malignancy9,11,12. Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory13,14 and exhaustion15,16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses. Disruption of TET2 increases the antitumour efficacy of CAR T cells, but establishes an epigenetic state that is prone to hyperproliferation and accumulation of secondary mutations.