TET2 regulates early and late transitions in exhausted CD8 <sup>+</sup> T cell differentiation and limits CAR T cell function
Alexander J. Dimitri, Amy E. Baxter, Gregory M. Chen, Caitlin R. Hopkins, Geoffrey T. Rouin, Hua Huang, Weimin Kong, Christopher Holliday, Volker Wiebking, Robert L. Bartoszek, Sydney Drury, Katherine Tuite-Dalton, Owen Koucky, Zeyu Chen, Josephine R. Giles, Alexander T. Dils, In-Young Jung, Roddy S. O’Connor, Sierra M. Collins, J.K. Everett, Kevin R. Amses, Scott Sherrill-Mix, Aditi Chandra, Naomi Goldman, Golnaz Vahedi, Julie K. Jadlowsky, Regina M. Young, J. Joseph Melenhorst, Shannon L. Maude, Bruce L. Levine, Noelle V. Frey, Shelley L. Berger, Stephan A. Grupp, David L. Porter, Friederike Herbst, Matthew H. Porteus, Shannon A. Carty, Frederic D. Bushman, Evan W. Weber, E. John Wherry, Martha S. Jordan, Joseph A. Fraietta
Abstract
CD8 + T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting TET2 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 TET2- targeted CAR T cells by disrupting TET2 via knock-in of a safety switch alongside CAR knock-in at the TRAC locus. TET2 -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.