Projects

Work in the lab is funded by Cancer Research UK and the European Research Council

We work on the crosstalk between immune cells and non-immune cells in lymph nodes to understand how lymph node remodelling is controlled during adaptive immune responses. We focus  on the role of dendritic cells and their interactions with the fibroblastic reticular cell network. Through this work on fundamental immune mechanisms, we discover pathways directly relevant to tumour microenvironments, such as dendritic cell migration and tumour infiltration, contractility mechanisms in cancer-associated fibroblasts and extracellular matrix remodelling.

Lymph Node Remodelling

Lymph node swelling (LN) is a classical hallmark of immunity. This expansion is observed by doctors, researchers and patients, yet as obvious as this process is, our understanding of the remodelling mechanisms involved are in their infancy. Lymph node remodelling is rapid and yet completely reversible, occurring countless times throughout our lifetimes.

The architecture of lymphoid organs is key to the effective operation of our immune system and is dictated by structures formed by non-haematopoetic stromal cells, including endothelial cells, and fibroblasts. Beyond their structural roles, stromal cells play an active role in immune responses, and the field of stromal immunology has become one of the most dynamic and exciting areas of immunology research.

In the lab we focus on the changing behaviour of fibroblastic reticular cells (FRCs) throughout cycles of lymph node remodelling. The purpose of this project is to understand how lymph node remodelling occurs and is resolved, repeatedly; to understand immunity in a whole organ context. We use a range of models from FRC cell lines to in vivo studies studying the whole organ. We are especially interested in how the function of FRCs is directed by their interactions with neighbouring immune cells such as the arriving antigen-bearing dendritic cells.

Media (left): Vibrotome cute section of lymph node showing vessels. (right): Serial z-sections through a vessel within the lymph node. Cell membranes are shown in red, centre/nucleus of FRCs is shown in green.

 (Right): Schematic showing Lymph node expansion time course, and below, the changing organisation of the fibroblastic reticular cell network

Podoplanin (PDPN) Expression

PDPN expression is normally restricted to specific cell types such as FRCs and lymphatic endothelium. However, many tumour types over-express PDPN. PDPN+ tumours correlate with poor prognosis and increased invasion and metastasis. Our previous work on PDPN function shows that PDPN controls contractility of fibroblasts and that crosstalk between PDPN+ cells and DCs inhibits the contractile function of PDPN.

This project investigates additional functions of PDPN in FRCs and other cell types including cancer cells and how these functions are modulated by interactions with DCs.

Tumour Immunology

The interplay between DCs and stroma is relevant to cancer in several ways.  There is significant overlap in both phenotype and function of fibroblastic reticular cells (FRCs) and carcinoma-associated fibroblasts (CAFs). Both are highly contractile specialised fibroblasts, and have significant roles in extracellular matrix organisation and controlling the behaviour of neighbouring cells in the microenvironment.

Many cancer cells escape primary tumours and spread via lymphatic vessels to draining LNs. LN metastases will be in close proximity to FRCs and leukocytes. The interplay between cancer cells and lymphoid stroma is an unaddressed question in both stromal immunology and cancer biology, but of significant impact to both fields.

The purpose of this project is to translate our understanding of the function of FRCs in lymphoid organs to give us parallel insights into the function and origins of CAFs in the tumour microenvironment

We collaborate with the talented Tape lab also at UCL –  to investigate the reciprocal signalling between fibroblasts and dendritic cells using phosphoproteomics.