Synapse - TET2 guards against unchecked BATF3-induced CAR T cell expansion

TET2 guards against unchecked BATF3-induced CAR T cell expansion Journal Article

Authors:	Jain, N.; Zhao, Z.; Feucht, J.; Koche, R.; Iyer, A.; Dobrin, A.; Mansilla-Soto, J.; Yang, J.; Zhan, Y.; Lopez, M.; Gunset, G.; Sadelain, M.
Article Title:	TET2 guards against unchecked BATF3-induced CAR T cell expansion
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. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords:	controlled study; protein expression; ten eleven translocation 2; unclassified drug; dna binding protein; tet2 protein, human; human cell; somatic mutation; genetics; dna-binding proteins; nonhuman; cell proliferation; mouse; metabolism; allele; gene; protein depletion; animal experiment; animal model; transcription factor; cell differentiation; acute lymphoblastic leukemia; risk assessment; prostate cancer; lymphocyte differentiation; lymphocyte activation; cellular immunity; antigen; epigenetics; gene disruption; genomic instability; myc protein; hematopoiesis; immunity; tumor; tumor rejection; adoptive immunotherapy; cell expansion; immunotherapy, adoptive; differentiation; regulator protein; immunological memory; memory t lymphocyte; translocation; cell; genetic regulation; transcription factor ap 1; cell engineering; dioxygenase; cancer; humans; human; male; female; article; cell reprogramming technique; chimeric antigen receptor t-cell immunotherapy; induced response; receptors, chimeric antigen; dioxygenases; transcription factor batf3
Journal Title:	Nature
Volume:	615
Issue:	7951
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2023-03-09
Start Page:	315
End Page:	322
Language:	English
DOI:	10.1038/s41586-022-05692-z
PUBMED:	36755094
PROVIDER:	scopus
PMCID:	PMC10511001
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85147656987&doi=10.1038%2fs41586-022-05692-z&partnerID=40&md5=69329685594c38e8d7dc4a258ce00af8
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK author Michel Sadelain -- Source: Scopus