TET2 防止 BATF3 诱导的 CAR-T 细胞失控扩增

Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies 1-5 . As T cell differentiation and functional states are associated with distinct epigenetic profiles 6,7 , 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 memory 9,10 , albeit not cause malignancy 9,11,12 .

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 memory 13,14 and exhaustion 15,16 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.