Enhancing T cell immunotherapy through dosing of memory transcription factors

T cell therapies hold promise for treating solid tumours, but their efficacy is limited by poor persistence of transferred cells. Previous strategies to enhance persistence often relied on enforcing constitutively activated, and hence potentially toxic or oncogenic, T cell states. In contrast, physiological immune responses are sustained by quiescent, self-renewing progenitor T cells that depend on the memory transcription factor BACH2. These cells maintain stem-like potential while giving rise to short-lived effector cells. Here, I show that quantitative control of BACH2 dosage governs the physiological continuum of stem and effector CD8+ T cell states, a principle that can be leveraged to engineer synthetic states with superior persistence and anti- tumour activity. Under physiological conditions, BACH2 is precisely regulated in CD8+ T cells, with intermediate expression in memory and progenitor-exhausted subsets. Enforcing excessive levels of BACH2 locks cells in a quiescent state, disrupting the acquisition of effector functions necessary for tumour control. By contrast, low-dose BACH2 permits effector differentiation while preserving stem-like features, thereby enhancing persistence and therapeutic efficacy. Mechanistically, low-dose BACH2 partially restrains AP-1 occupancy at enhancers, attenuating highly AP-1–dependent genes without interfering with effector programmes. This dosage principle extends to other memory factors, as low-dose FOXO1 expression also augments T cell responses in an analogous manner. Thus, memory factor dosage emerges as a key regulator of T cell fate, suggesting that quantitative tuning of gene expression can drive qualitative improvements in cancer immunotherapy.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Conti Negrin, Alberto

Advisor dc:contributor.advisor

• Roychouhduri, Rahul

• Immunotherapy
• T cell
• Transcription factor
• BACH2

Licence

• https://www.repository.cam.ac.uk/bitstreams/d1cb20e8-217f-42b7-a9b9-fa573784a56e/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.126128

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/396870