Mass cytometry images of carcinogen induced lung tumours in mice.

Julian Downward : Investigating mechanisms by which oncogenic Ras signalling promotes the ability of tumours to evade the immune system

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Activated RAS signaling in tumours promotes the ability of tumour to avoid destruction by the immune system. As immune evasion is critical to the development of a tumour, it is likely that several different mechanisms have been hijacked by the cancer cell to enable this. It appears that Ras signaling directly controls a number of these.

RAS mutant tumours are able to survive in an immune competent host, despite bearing a high mutational burden, due in part to the ability of oncogenic RAS signalling to suppress the immune system locally. By analyzing gene expression patterns driven by RAS oncogenes in tumours, we have identified several mechanisms whereby RAS may be suppressing immune function. One such mechanism is the ability of RAS to stabilize the mRNA of PD-L1, the immune checkpoint receptor ligand, though a mechanism involving control of the AU rich element binding protein tristetraprolin. (Coelho et al., Immunity 2017)

Several other mechanisms of immune suppression driven by RAS are being investigated. We are interested in figuring out the best way to combine therapies that target RAS signaling pathways within the cancer cell and those that remove immune evasion mechanisms, with the hope of being able to eradicate residual disease after initial tumour regression.