AbstractAlthough there have been major advances in cancer therapeutics, ovarian cancer remains the fifth deadliest malignancy among women. Patients with ovarian cancer experience increased levels of psychological stress with pre-clinical evidence suggesting that adrenergic stress influences tumour progression with an increased tumour burden, metastasis and angiogenesis. The immune regulation plays an important role in ovarian cancer. In the interface between cancer and immune cells, a crucial role has the interaction between the programmed cell death protein 1 (PD-1) on immune cells and the programmed cell death protein ligand (PD-L1) on cancer cells. This interaction creates an immunosuppressive microenvironment in which the tumour can escape the immune response. This research aims to explore the effects of adrenergic stress, mediated by Noradrenaline (NA), on the immune regulation of PD-L1 and how this influences the immunotherapy targeting the PD-(L)1 axis.
PD-L1 expression was evaluated on ovarian cancer cell lines and on tissues derived from ovarian cancer patients. The adrenergic regulation was examined in vitro by treating either ovarian cancer or immune cells with NA and using Propranolol (PRO), a non-selective betablocker, to inhibit the adrenergic signalling. To investigate the molecular mechanism regulating the immune-cancer interactions, in vitro experiments included co-culture of immune and cancer cells in a 2D trans-well model and in a 3D spheroid model. A syngeneic mouse model of ovarian cancer was used to test a combined therapy of PRO and a PD-(L)1 inhibitor. C57BL/6 mice were injected with ovarian cancer cells and underwent chronic restraint stress. Tumour burden, metastatic nodules, and the immune signature were evaluated.
Adrenergic stress was shown to have a role in the regulation of the immune response to cancer. In particular, the adrenergic stress blockade with PRO reduced the levels of IFN-γ, a pro-inflammatory cytokine which upregulates PD-L1 expression on ovarian cancer cells. In the 3D spheroid model of ovarian cancer, PRO increased the immune infiltration into the tumour mass. The syngeneic in vivo mouse model showed that a combined therapy of PRO and PD-(L)1 inhibitor decreased tumour burden, metastatic nodules and increased the antitumour immune signature.
In summary, this study demonstrates that the adrenergic stress has a negative impact on ovarian cancer and this is mediated – among other processes - by the regulation of the immune response. Furthermore, a combined therapy of PRO and PD-(L)1 inhibitor could represent a potential therapeutic strategy for ovarian cancer patients.
|Date of Award||Oct 2019|
|Supervisor||Melanie Flint (Supervisor)|