Study of immune cell responses to early carcinogenesis

Lung cancer is the most common cancer world-wide and curative therapy is only possible in a very low proportion of patients. Carcinoma in-situ lesions have been shown to regress or progress to invasive cancer and there is evidence that immune cells play a crucial role in this. T-cell exhaustion, a state of T-cell dysfunction, might contribute to this, preventing immune control of tumours. The pathways for this remain to be fully defined.

The recent development of a highly-efficient, genetically-modifiable, 3D human embryonic lung culture system as well as the isolation of primary human foetal lung immune cells and their subtypes, enables us to look at how foetal and adult immune cells respond to early carcinogenesis in vitro. We will start by introducing KRAS mutations in the 3D epithelial organoid system and then studying the response of both epithelial and immune cells upon co-culture. Analysis will be by immunohistochemistry, scRNAseq and live cell imaging. This will give us the opportunity, for the first time, to study how immune cells respond to early carcinogenesis in vitro. This proposed work will identify mechanisms of immune evasion and tumour control as well as track the earliest phases of carcinogenesis-associated T cell dysfunction, providing the basis for future immunomodulatory therapy for both pre-malignant and malignant disease.