WEHI Wednesday Seminar hosted by Dr Stephin Vervoort

Dr Dáire Gannon

Research Officer – Vervoort Laboratory, Genetics and Gene Regulation division, WEHI

CBP targeting exploits paralog asymmetry to enhance anti-cancer immunity

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

Adoptive T cell therapies can induce durable cancer regression for the treatment of certain hematological malignancies, but their efficacy can be limited by poor persistence and T cell exhaustion. In collaboration with researchers at PeterMac, ONJ and across WEHI, we have discovered non-redundant functions for the paralogous acetyltransferases CBP and p300 in regulating CD8⁺ T cell fate, revealing therapeutically exploitable paralog asymmetry. Chemical screening, endogenous degron models and integrated transcriptomic and epigenomic profiling, demonstrates that selective CBP depletion promotes memory/stem-like T cell states. CBP degradation destabilized effector and exhaustion-associated chromatin states while sparing memory-associated programs through P300-mediated buffering. Integrative chromatin analyses identified enrichment of STAT family motifs at CBP-dependent regions and STAT1 disruption similarly promoted memory-like differentiation. Transient CBP perturbation during ex vivo T cell activation enhanced persistence and anti-tumour activity following adoptive transfer across multiple tumour models, including chimeric antigen receptor (CAR) T cell therapies. A CBP-selective Proteolysis Targeting Chimera (PROTAC) phenocopied these effects, further supporting CBP as the principal paralog controlling this differentiation program. Together, these findings identify the specific activities of CBP as a mechanism regulating T cell fate and anti-tumour immunity.
 

Finally, future research directions will be discussed, including plans to leverage the Vervoort laboratory’s high-throughput precision screening platform. 

All welcome!