The C-C chemokine receptor 5 (CCR5) is a 7-transmembrane G-protein coupled
receptor primarily involved in the immune response, but its multifaceted properties
have been linked with many diseases. CCR5 expression has been reported on cancer
cells, influencing cancer progression, by affecting cell proliferation and metabolic-
reprogramming. These findings have been used to repurpose CCR5 antagonist
(Maraviroc) to target cells within the tumour microenvironment, but so far with not
much success. Since little is known about the molecular cell biology mechanisms
driving endogenous CCR5 activity in cancer cells, further investigations are required
before targeting CCR5 for cancer therapy.
We use a range of biological approaches and the development of chemical tools to
understand the presentation and mechanistic functioning of CCR5 on prostate cancer
(PCa) cells. Our findings confirm endogenous expression of CCR5 on PCa cells but
reveal alternative receptor presentation compared to previously studied transfected
and primary immune cells. We also demonstrate that CCR5 interaction with its
agonists on PCa cells do not trigger receptor internalisation, but induce activation of
downstream signalling pathways that leads to cell functional effect with the release of
chemokines. However, conventional tools are not sufficient for understanding the role
of low expressing endogenous CCR5. In order to define the alternative behaviour of
CCR5 on PCa cells, we have optimised the use of organocatalyst-mediated protein
aldol ligation (OPAL) and Conjugate addition/ring expansion (CARE) chemistry to
develop novel chemokine analogues and chemically modified CCL5 derivatives to
isolate agonist-bound receptor complexes, probe for CCR5 activation, and potentially
lead to chemokine-based therapeutics.
Overall, findings from my thesis expose unique functional characteristics of CCR5 in
cancer cell lines, inferring a cell-type-dependent behaviour for this receptor. Therefore,
understanding the factors that govern CCR5 behaviour could inform strategies to
target CCR5 for cancer therapies.
