Selection is the most powerful force in cancer evolution, because it leads to adaptation.
It is adaptation that allows cancer cells to survive harsh conditions such as low oxygen, nutrients, or pH, and entirely different environments encountered in the process of forming metastases.
Two principle sources of selection are the tumour microenvironment (TME) and the treatment given to patients. In the context of renal cancer, the frequent loss of VHL induces a pseudo-hypoxic state which results in enhanced angiogenesis and highly vascularized tumours. In addition, renal cancers are highly infiltrated by immune cells. The majority of infiltrating immune cells are CD4+helper T cells and cytotoxic CD8+ T cells, some of which show an exhausted phenotype, characterized by upregulation of inhibitory receptors, suggesting they are reacting to antigens presented on tumour cells.
Renal cancers exhibit distinct and highly conserved evolutionary trajectories (Turajlic et al. Cell 2018a) and we hypothesise that these are associated with distinct TME conditions that constrain the potential evolutionary paths available to tumours.
The importance of the TME is further underlined by the fact that most approved therapies of renal cancer target the TME: include small molecule inhibitors and monoclonal antibodies (mAb) targeting VEGF and mAbs targeting inhibitory receptors on T cells (eg PD-1 or CTLA-4).
A significant portion of patients do not benefit from either approach, therefore TME understanding and manipulation can be of profound clinical benefit. We use interventional studies (example to analyse the changes in the TME induced by these drugs to inform combinatorial therapies and alternative approaches.