Targeting IFN-γ-induced dedifferentiation in melanoma as an immune evasion strategy

Project Outline

Immune checkpoint inhibitors have had a dramatic effect on surviving melanoma. However, not everyone is cured. Melanoma cells become resistant to checkpoint blockade therapy by slipping into embryo-like, “neural-crest” transcriptional cell states that hide immune targets. Recent work shows that prolonged interferon-gamma (IFN-γ) —an inflammatory signal released during anti-tumour immune responses — can lock melanoma into this dedifferentiated state. We aim to understand and reverse that switch.

This PhD will investigate how IFN-γ–responsive genes that are central to neural crest biology, help melanoma cells adopt and maintain a resistant identity. Using well-characterised human and mouse cell models, the student will perturb these genes (e.g. gene knock-down/CRISPR, small molecule inhibitors or blocking antibodies where appropriate) and measure effects on melanoma differentiation markers, survival under inflammatory stress, vulnerability to cytotoxic T-cell attack, and tumour growth in vivo. Methodologies will include flow cytometry, multiplex imaging, transcriptomics (bulk RNA-seq), functional T-cell co-culture assays, and in vivo tumour transplantation models.

Training spans cancer cell biology, immunology, in vivo studies and data science, with opportunities to learn transcriptomic and spatial analyses and work within a collaborative basic-preclinical environment that has established strong ties with the clinic. By defining which IFN-γ–induced factors keep melanoma in an immune-evasive state — and how to switch them off, this project could inform combination strategies that restore tumour differentiation and improve responses to immunotherapy.

Applications for this project are now open. Please complete your application on The University of Manchester website.