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Access through your institution Buy or subscribe Several factors have been proposed to account for the restricted efficacy of chimeric antigen receptor (CAR) T cell therapies to certain

patient subgroups. One such factor is T cell exhaustion in response to chronic antigen stimulation. A new study in _Nature_ describes that overexpression of the AP-1 family transcription

factor JUN by CAR T cells renders them resistant to exhaustion and improves tumour control in mouse models, which could have important clinical implications. These epigenetic changes were

associated with enrichment of AP-1–bZIP and bZIP–IRF transcription factor binding motifs in exhausted HA-28z CAR T cells and increased levels of bZIP and IRF transcription factors (such as

JUNB, BATF3 and IRF4). It is known that whereas the canonical AP-1 heterodimer FOS–JUN drives T cell activation, other bZIP and IRF family members can have opposite effects. The authors

therefore hypothesized that the exhaustion of HA-28z CAR T cells might result from a relative deficiency of FOS–JUN compared with these other factors. They showed that JUN overexpression

increased cytokine production and the frequency of memory versus effector populations in JUN-HA-28z CAR T cells but not JUN-CD19-28z CAR T cells, which shows that JUN overexpression is of

greater functional relevance in the exhausted T cells that express high levels of bZIP and IRF family members. JUN-HA-28z CAR T cells had a markedly altered transcriptome compared with

HA-28z CAR T cells, with the differentially expressed genes being enriched for AP-1 family binding sites. Further experiments using various JUN mutants showed a crucial role for dimerization

of JUN but not the activation of transcription in mediating the effects of JUN overexpression, which suggests that JUN disrupts or displaces the immunoregulatory bZIP and IRF

transcriptional complexes from exhaustion-associated genes. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access

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local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES ORIGINAL

ARTICLE * Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. _Nature_ 576, 293–300 (2019) Article  CAS  Google Scholar  RELATED ARTICLE * Blank, C. U. et

al. Defining ‘T cell exhaustion’. _Nat. Rev. Immunol._ 19, 665–674 (2019) Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nature Reviews

Immunology http://www.nature.com/nri/ Kirsty Minton Authors * Kirsty Minton View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to Kirsty Minton. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Minton, K. Overcoming CAR T cell exhaustion. _Nat Rev Immunol_ 20, 72–73

(2020). https://doi.org/10.1038/s41577-019-0265-x Download citation * Published: 16 December 2019 * Issue Date: February 2020 * DOI: https://doi.org/10.1038/s41577-019-0265-x SHARE THIS

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