Author
Listed:
- Nayan Jain
(Memorial Sloan Kettering Cancer Centre
Memorial Sloan Kettering Cancer Centre)
- Zeguo Zhao
(Memorial Sloan Kettering Cancer Centre)
- Judith Feucht
(Memorial Sloan Kettering Cancer Centre
University Children’s Hospital)
- Richard Koche
(Memorial Sloan Kettering Cancer Centre)
- Archana Iyer
(Memorial Sloan Kettering Cancer Centre)
- Anton Dobrin
(Memorial Sloan Kettering Cancer Centre
Memorial Sloan Kettering Cancer Centre)
- Jorge Mansilla-Soto
(Memorial Sloan Kettering Cancer Centre)
- Julie Yang
(Memorial Sloan Kettering Cancer Centre)
- Yingqian Zhan
(Memorial Sloan Kettering Cancer Centre)
- Michael Lopez
(Memorial Sloan Kettering Cancer Centre)
- Gertrude Gunset
(Memorial Sloan Kettering Cancer Centre)
- Michel Sadelain
(Memorial Sloan Kettering Cancer Centre)
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.
Suggested Citation
Nayan Jain & Zeguo Zhao & Judith Feucht & Richard Koche & Archana Iyer & Anton Dobrin & Jorge Mansilla-Soto & Julie Yang & Yingqian Zhan & Michael Lopez & Gertrude Gunset & Michel Sadelain, 2023.
"TET2 guards against unchecked BATF3-induced CAR T cell expansion,"
Nature, Nature, vol. 615(7951), pages 315-322, March.
Handle:
RePEc:nat:nature:v:615:y:2023:i:7951:d:10.1038_s41586-022-05692-z
DOI: 10.1038/s41586-022-05692-z
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