Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.

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Publication Details

Journal
Nature Immunology
Published
2026-01-16
DOI
https://doi.org/10.1038/s41590-025-02389-z
Citations
3
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
72.59

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article

Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

Panagiota Vardaka, RANDY GREAVES, Ian A. Parish, Charlotte J. Imianowski et al.
3 citations
Nature Immunology
CAR-T cell therapy research
72.59
article

Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

Panagiota Vardaka, RANDY GREAVES, Ian A. Parish, Charlotte J. Imianowski, Teresa von Linde, Rahul Roychoudhuri, Christian Deo T. Deguit, J. Yang, Klaus Okkenhaug, Oliver T. Burton, Shienny Sampurno, Yumi Yamashita-Kanemaru, Iván Pérez-Núñez, Bartłomiej Świątczak, Sarah K. Whiteside, Alexander C. Evans, Suman K. Mitra, Alexander J. Wesolowski, Alberto G. Conti, Ardon M. Pillay, Aws Al-Deka, Jack Chapman, Layla Dahmani, Nicole Y. L. Saw
article en
3 citations

Abstract

Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.

Nature ImmunologyVol. 27(3)
Centre National de la Recherche Scientifique (FR), Inserm (FR), The University of Melbourne (AU), University of Dundee (GB), Université de Lille (FR), University of Cambridge (GB), Peter MacCallum Cancer Centre (AU), Centre Hospitalier Universitaire de Lille (FR), University of Oxford (GB), Cambridge School (PT)
Cancer Research UK, Australian Cancer Research Foundation, Fondation ARC pour la Recherche sur le Cancer, Peter MacCallum Cancer Centre, Medical Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 0%
CAR-T cell therapy research
72.59
DOIOpen Access PDFOpenAlex
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