Defining stroma function in the developing tumour microenvironment

Our immune system is our primary defence mechanism, but tumours have developed strategies to interfere with almost every step necessary for our immune system to recognise and destroy cancer cells. The recent success of immunotherapy, which aim to ‘kick start’ our immune system hold great promise, but currently are effective in just a few cancer types, with many patients not responding. Understanding how a tumour is able to evade and switch off our immune system during its development will be key to the development of improved treatments and the design of new, targeted therapies. A tumour contains many non-cancer cells that are critical to support the tumour as it develops. One of these populations, the cancer associated fibroblast, is emerging as a key promoter of tumour inflammation, but little is known about the how, when or who they act upon in a tumour, or how they prevent therapies from working. This programme uses state-of-the-art technologies to address these problems. Using such an integrative approach we aim to uncouple the networks governing the suppressive function of cancer-associated fibroblasts, and to exploit these findings to develop new or improved approaches to cancer therapy.

Our immune system is our primary defence mechanism destroying both exogenous and endogenous threats, but tumours have developed strategies to interfere with almost every step necessary for a successful anti-tumour immune response. The recent success of immunotherapy platforms to harness and reactivate the immune response represent a major therapeutic advancement, however, current approaches are effective in just a few cancer types, and many patients still fail to respond or do not see lasting benefits. Increasing our understanding of anti-tumour immunity and the suppressive networks at play during the different stages of malignant transition will be fundamental to the development of improved strategies and design of new, targeted therapeutic platforms. The supporting tumour stroma, particularly cancer associated fibroblasts (CAFs) are emerging as key sources of tumour-promoting inflammation, but little is known about the mechanisms by which these cells act, when in tumour evolution these functions are acquired, or how they may contribute to therapeutic resistance. This programme takes a multidisciplinary approach, integrating experimental cancer models, complex in vitro and in silico systems, high throughput genomics and bioinformatics to explore the mechanisms and evolution of stromal-mediated immune dysfunction in the tumour microenvironment. Focusing on a subset of CAFs and their counterparts at tumour draining lymph nodes, which express the glycoprotein podoplanin, we aim to uncouple the immunoregulatory systems governing their suppressive function.