TET2 regulates early and late transitions in exhausted CD8 <sup>+</sup> T cell differentiation and limits CAR T cell function
CD8<sup>+</sup> 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<sub>EX</sub>) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like T<sub>EX</sub> progenitors toward terminally differentiated and effector (T<sub>EFF</sub>)-like T<sub>EX</sub>. TET2 also enforced a terminally differentiated state in the early bifurcation between T<sub>EFF</sub> and T<sub>EX</sub>, 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<sub>EX</sub> differentiation and can be targeted with a safety mechanism in CAR T cells for improved tumor control.
Authors
- Gregory M. Chen (ORCID: https://orcid.org/0000-0002-4083-5083)
- Matthew H. Porteus (ORCID: https://orcid.org/0000-0002-3850-4648)
- Martha S. Jordan (ORCID: https://orcid.org/0000-0003-2359-3227)
- Golnaz Vahedi (ORCID: https://orcid.org/0000-0002-2249-8247)
- Kevin R. Amses (ORCID: https://orcid.org/0000-0002-4470-104X)
- Owen Koucky
- J.K. Everett (ORCID: https://orcid.org/0000-0002-9200-9322)
- Frederic D. Bushman (ORCID: https://orcid.org/0000-0003-4740-4056)
- Scott Sherrill-Mix (ORCID: https://orcid.org/0000-0002-8955-8072)
- Aditi Chandra (ORCID: https://orcid.org/0000-0002-2053-163X)
- Bruce L. Levine (ORCID: https://orcid.org/0000-0001-6971-8465)
- Shelley L. Berger (ORCID: https://orcid.org/0000-0001-5398-4400)
- Joseph A. Fraietta (ORCID: https://orcid.org/0000-0001-7900-8993)
- Friederike Herbst (ORCID: https://orcid.org/0000-0002-2167-750X)
- Evan W. Weber (ORCID: https://orcid.org/0000-0001-5039-2899)
- Alexander T. Dils (ORCID: https://orcid.org/0000-0002-9052-4726)
- Roddy S. O’Connor (ORCID: https://orcid.org/0000-0001-5645-4544)
- Naomi Goldman (ORCID: https://orcid.org/0000-0003-0721-3087)
- Caitlin R. Hopkins (ORCID: https://orcid.org/0000-0001-6905-8268)
- Geoffrey T. Rouin (ORCID: https://orcid.org/0009-0000-1318-2059)
- Alexander J. Dimitri (ORCID: https://orcid.org/0000-0002-7337-3196)
- Shannon L. Maude (ORCID: https://orcid.org/0000-0003-2210-8736)
- Sydney Drury (ORCID: https://orcid.org/0000-0002-5614-0796)
- E. John Wherry (ORCID: https://orcid.org/0000-0003-0477-1956)
- J. Joseph Melenhorst (ORCID: https://orcid.org/0000-0001-7677-537X)
- In-Young Jung (ORCID: https://orcid.org/0000-0003-3004-8083)
- Sierra M. Collins (ORCID: https://orcid.org/0000-0002-8174-9659)
- Shannon A. Carty (ORCID: https://orcid.org/0000-0003-2286-8014)
- Josephine R. Giles (ORCID: https://orcid.org/0000-0002-3713-338X)
- Stephan A. Grupp (ORCID: https://orcid.org/0000-0001-8030-7595)
- Regina M. Young (ORCID: https://orcid.org/0000-0002-0158-9449)
- Robert L. Bartoszek (ORCID: https://orcid.org/0000-0003-1417-4661)
- Julie K. Jadlowsky (ORCID: https://orcid.org/0009-0005-5115-1321)
- Amy E. Baxter (ORCID: https://orcid.org/0000-0002-1555-0713)
- Volker Wiebking (ORCID: https://orcid.org/0000-0002-9429-5254)
- Hua Huang (ORCID: https://orcid.org/0000-0002-8936-3371)
- Weimin Kong (ORCID: https://orcid.org/0000-0001-9591-5390)
- Noelle V. Frey (ORCID: https://orcid.org/0000-0003-3688-9836)
- Zeyu Chen (ORCID: https://orcid.org/0000-0001-8534-0829)
- Katherine Tuite-Dalton (ORCID: https://orcid.org/0000-0001-6934-3341)
- David L. Porter (ORCID: https://orcid.org/0000-0002-0748-8374)
- Christopher Holliday
Institutions
- Children's Hospital of Philadelphia (US)
- California Institute for Regenerative Medicine (US)
- University of Michigan (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Parker Institute for Cancer Immunotherapy (US)
- Translational Therapeutics (United States) (US)
- University of Pennsylvania (US)
- Michigan State University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1126/sciadv.adp9371
- Citations
- 19
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 5.37
Funders
- National Science Foundation
- University of Pennsylvania