TET2 guards against unchecked BATF3-induced CAR T cell expansion

Nayan Jain, Zeguo Zhao, Judith Feucht, Richard Koche, Archana Iyer, Anton Dobrin, Jorge Mansilla-Soto, Julie Yang, Yingqian Zhan, Michael Lopez, Gertrude Gunset and Michel Sadelain ()
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Nayan Jain: Memorial Sloan Kettering Cancer Centre
Zeguo Zhao: Memorial Sloan Kettering Cancer Centre
Judith Feucht: Memorial Sloan Kettering Cancer Centre
Richard Koche: Memorial Sloan Kettering Cancer Centre
Archana Iyer: Memorial Sloan Kettering Cancer Centre
Anton Dobrin: 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

Nature, 2023, vol. 615, issue 7951, 315-322

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05692-z

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