TET2 regulates early and late transitions in exhausted CD8 ⁺ T cell differentiation and limits CAR T cell function

Abstract

CD8⁺ T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting <i>TET2</i> in CAR T cells provides therapeutic benefit; however, TET2's role in exhausted T cell (T_EX) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like T_EX progenitors toward terminally differentiated and effector (T_EFF)-like T_EX. TET2 also enforced a terminally differentiated state in the early bifurcation between T_EFF and T_EX, indicating broad roles for TET2 in acquisition of effector biology. To exploit the therapeutic potential of TET2, we developed clinically actionable <i>TET2-</i>targeted CAR T cells by disrupting <i>TET2</i> via knock-in of a safety switch alongside CAR knock-in at the <i>TRAC</i> locus. <i>TET2</i>-targeted CAR T cells exhibited restrained terminal exhaustion in vitro and enhanced antitumor responses in vivo. Thus, TET2 regulates fate transitions in T_EX differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.