Immunotherapy is revolutionizing cancer treatment by offering unprecedented long-term survival. However, its effectiveness is limited by tumour heterogeneity, drug resistance, immune evasion and the tumour microenvironment’s immunosuppressive nature. Immune reprogramming strategies targeting oncogenic transcriptional networks and enhancing immune surveillance are a promising way of overcoming these challenges.
Our laboratory has demonstrated that the transcription factors PU.1, IRF8 and BATF3 (PIB) have the ability to reprogram both human and murine fibroblasts, as well as tumour cells, into cDC1-like antigen-presenting cells. This process elicits potent anti-tumour responses and renders tumours susceptible to immune checkpoint blockade in vivo. However, the efficiency of reprogramming varies across tumour types, and the structural and mechanistic basis by which PIB cooperatively engages with chromatin to drive cDC1 identity remains unknown.
This project aims to define the nucleosome-binding logic, transcriptional cooperativity, and structural mechanisms underlying PIB-mediated chromatin remodeling. Using high-resolution cryo-electron microscopy, genome-wide chromatin accessibility and transcriptional profiling, and biochemical assays, we will investigate how PIB interacts with nucleosomes to activate immunogenic programmes. These insights will inform the rational design of synthetic transcription factors to improve immune reprogramming and establish a new platform for next-generation cancer immunotherapies.
For further information about this HALRIC pilot project, please contact:
Sandhya Malla
Lund University
sandhya.malla@med.lu.seFilipe Pereira
Lund University
filipe.pereira@med.lu.se
