The role of innate immunity in pancreatic cancer progression and treatment
Immune cells are highly abundant in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) and they significantly influence the entire process of PDAC tumourigenesis. While the anti-tumour response is typically mediated by adaptive immunity, cells of the innate immune system can significantly influence this anti-tumour response and in some cases dictate response to treatment. This thesis presents work on two projects – the first project is focussed on characterizing the immunomodulatory effects of gemcitabine in combination with an Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (Gem/ATRi) in pancreatic cancer, whereas the second project describes the pro-tumourigenic role of type 2 innate lymphoid cells (ILC2s) in PDAC.
In chapter 3, Gem/ATRi showed preclinical efficacy in the ‘T cell high’ 2838c3 tumour model and induced dendritic cell (DC) activation in both the tumour and draining lymph node (LN). This was associated with a substantial depletion of all intratumoural DC subsets in the tumour and a selective depletion of LN-resident DCs in the dLN. Gem/ATRi similarly caused a depletion of intratumoural CD8+ T cells, but of the remaining population there was a decrease in the proportion of exhausted cells along with an increased proportion of proliferating cells. Experiments using the ‘T cell low’ 6419c5 tumour model revealed that cDC1 in these tumours were dysfunctional and unresponsive to stimulation compared to those in 2838c3 tumours.
In chapter 4, I demonstrated the pro-tumourigenic role of ILC2s in PDAC and investigated mechanisms that potentially underlie this observation. ILC2 deletion significantly extended the survival of 2838c3-bearing mice and altered the intratumoural immune infiltrate. Attempts to pinpoint the mechanism(s) underlying the pro-tumourigenic role of ILC2s (i.e. IL-33, IL-13, eosinophils, NK cells and the ILC2-OX40L-Treg axis) did not yield any positive results, although it is clear that they modulate tumour growth via an effect on adaptive immunity. Further experiments involving CD8+ T cell depletion in ILC2-deficient mice revealed that ILC2s influence tumour growth via both CD8+ T cell-dependent and independent mechanisms. Finally, the impact of ILC2 deletion on PDAC tumour growth was found to be dependent on tumour cell-intrinsic factors, possibly on those that dictate the strength of the baseline anti-tumour CD8+ T cell response.