The effect of angiotensin receptor blockers on cancer associated fibroblasts as a potential cancer therapy adjuvant

The tumour microenvironment (TME) harbours conditions that render current cancer therapies less effective. High levels of fibrosis from stromal cells can encourage poor vascular construction and can increase interstitial fluid pressure (IFP) in the tumour, both of which can negatively affect vascular perfusion. Impaired vascular perfusion can limit drug distribution throughout the tumour. Further, areas near faulty vasculature can become low in oxygen, or hypoxic, which directly inhibits radiation therapy efficacy. Fibrosis can also cause tumoural stiffness, which is correlated with worse patient response to treatment and worse survival. Possible adjuvant cancer therapies that aim to target fibrosis may also improve vascular perfusion and decrease tumoural stiffness, which could enhance the efficacy of existing cancer treatments. Angiotensin receptor blockers (ARBs), are a widely prescribed and well-tolerated group of antihypertensives, which have been reported to also have antifibrotic effects in liver, kidney, and heart diseases. In my work, I study the use of ARBs, as a putative antifibrotic to ameliorate cancer therapy efficacy. I first assess the use of ARBs and other antihypertensives within a retrospective study of patients with head and neck cancer. In this study, I hypothesize that the use of antihypertensives medications is correlated with improved patient survival (Chapter 2). Subsequently, I evaluate how one ARB, telmisartan, effects cancer associated fibroblasts (CAFs). In an in vivo tumour model, I study global transcriptional changes by employing the use of single-cell RNA-sequencing (scRNA-seq) on telmisartan-treated and control tumours from mouse xenografts (Chapter 3). Moreover, I extracted primary naïve dermal fibroblasts from mice and polarized them to specific states to study the effects of telmisartan on distinct fibroblast states ex vivo, analogous to CAF subtypes in the tumour (Chapter 4). Overall, my work shows that ARB use is correlated with improved head and neck cancer patient survival outcomes. Furthermore, I show that specific myofibroblast fibroblasts and myCAFs are responsive to telmisartan in both tumours and in ex vivo cells.