Edinburgh Cancer Research

Alan Serrels: Tumour Immune Environment

Cancer Research Programme

A.Serrels figure 1
Figure 1. Current understanding of FAK-dependent immune modulation in SCC tumours. Figure reproduced from Serrels A, Frame M.C, Oncoimmunology. 2016 Jan 13;5(4).

Reprogramming the tumour immune environment to promote an anti-tumour immune response has shown promise as a therapeutic approach in the fight against cancer. In preclinical murine models, targeting a variety of immune cell populations including macrophages and Tregs has shown anti-tumour efficacy either alone or when used in combination with agents that enhance CD8 T-cell activation. Our lab is interested in understanding how aberrantly regulated signalling pathways in cancer cells contribute to orchestrating the immuno-suppressive tumour environment, and how targeting these can be used to potentiate anti-tumour immunity either alone or in combination with other immunotherapies. In this context we have identified a new role for Focal Adhesion Kinase (FAK), a non-receptor protein tyrosine kinase frequently upregulated in cancer. Best known for its functions downstream of integrins and growth factors receptors, FAK can also translocate to the nucleus where its function remains poorly characterised.

A.Serrels - Research Programme 2
Figure 2. Multi-modal imaging of cancer. Top Left – Representative image showing GFP-labeled SCC cancer cells (Green), collagen matrix imaged using SHG (red), and a range of cell types including red blood cells (RBC), endothelial cells, and tumor infiltrating immune and stromal cells imaged using CARS (Cyan). Top right - Small region from the left image showing RBCs, endothelial cells lining a blood vessel (each cell body is marked with *) and infiltrating host cells (solid arrow). Bottom left –Small region from the top left image showing a tumor cell pushing out invadopodia or fillopodia (dashed arrow) through the perivascular collagen towards the endothelial lining (dashed line) of the adjacent blood vessel. This cell appears to be in contact with host cells (solid arrow). Bottom right – Small region from the top left image showing a group of cancer cells (solid arrow) that have invaded through the perivascular collagen (boundary delineated with dashed line) and are pushing on the endothelial cell wall of a blood vessel. Figure reproduced from Lee et al, Intravital, 4:1, 2015

We have recently identified that nuclear FAK can regulate the transcription of chemokines and cytokines important in controlling the anti-tumour immune response (Figure 1) (Serrels et al, Cell, 163, Sept 2015). Furthermore, comparison of nuclear FAK levels between Squamous Cell Carcinoma (SCC) cells and skin keratinocytes (the normal cell counterpart to the SCCs) has shown elevated levels of nuclear FAK in cancer cells, implying that oncogenic transformation may trigger its nuclear accumulation. Thus, FAK represents a new target for immunotherapy, and modulating its nuclear function may yield cancer specific responses. Understanding the extent and mechanistic basis of FAK-dependent immune modulation in cancer, and identifying optimal combinations with other immunotherapies are key aims of the lab. To address our research questions, we use a combination of cutting edge genome editing, gene expression analysis, proteomics, flow cytometry, and advanced intra-vital imaging (Figure 2).