The general theme of the lab is the understanding of cell signalling pathways and transcriptional mechanisms that regulate the functional polarisation of macrophages and dendritic cells (DC) in inflammation and immunity. Macrophage and DC activation by microbial pattern recognition receptors, such as Toll like receptors (TLRs), is critical for innate and adaptive immunity and has been extensively studied. However, these cells also play important roles in the resolution of inflammation, maintaining tissue homeostasis and immune-tolerance, but we understand relatively little about the signalling pathways and molecular mechanisms that mediate the functions of macrophages and DC in this context. In infectious diseases and cancer, these mechanisms promote evasion of protective immunity and disease progression. On the other hand, disregulation of these mechanisms may also lead to chronic inflammatory disease and autoimmunity.
Our previous work showed the prototypical pro-inflammatory transcription factor, Nuclear Factor-kappaB (NF-kappaB), actually has an important role in the resolution of inflammation by limiting macrophage activation during infection. In parallel studies, we showed that NF-kappaB activation in tumour-associated macrophages (TAM) maintained an anti-inflammatory phenotype associated with tumour progression and suppression of anti-tumour immunity. More recently, we discovered that IKKbeta-mediated activation of the canonical NF-kappaB pathway plays a critical role in the maturation of tolerogenic DC and regulatory T cell (Treg) conversion – required to maintain peripheral tolerance and immune homeostasis. Our ongoing studies are focused on further characterisation of the signalling pathways in macrophages and DC that dictate the balance between pro- and anti-inflammatory functions or immune-stimulatory versus immune-suppressive activity.
1) NF-kappaB and associated signalling pathways in the functional maturation of DC in tolerance and immunity (Lead contact; Toby Lawrence).
An image of DC (green) in the skin entering lymphatic vessels (red). These non-lymphoid tissue (NLT)-DC patrol the tissue and migrate to draining lymph nodes through lymphatics where they can present antigens to naïve T cells. In steady-state, this process is important for tolerance to antigens in the tissue. But the instructive signals that trigger NLT-DC maturation and migration in steady-state remain an enigma. This project aims to unravel these mechanisms and characterise the pathways that regulate tolerogenic DC functions.
2) Ontogeny and function of tumour-associated macrophages (TAM) and their contribution to cancer progression (Lead contact; Toby Lawrence).
Mice that have been injected with ovarian cancer cells that express firefly luciferase, which allows the imaging of tumour growth and distribution in live mice. Our studies have shown that ovarian cancer cells colonise the omentum, a small piece of adipose tissue in the upper left area of the abdomen. The omentum is densly populated by CD163-expressing macrophages. Image Toby Lawrence/CIML
Video of whole-mount imaging of the omentum with an ovarian tumour nodule (white), adipocytes are stained red and CD163+ macrophages in green). Our studies show that CD163+ macrophages in the omentum promote the invasive activity of ovarian cancer cells and disease progression. Our current work aims to unravel the axes of cross-talk between CD163+ macrophages and cancer cells that promotes invasive disease. Video Toby Lawrence/CIML
3) The role of IKKbeta activation downstream of oncogenic-driver mutations in shaping the immune-suppressive microenvironment in cancer (Lead contact; Nathalie Auphan-Anezin).
4) Autophagy and innate immune signalling in macrophages and DC (Lead contact; Magali Bebien).
Our lab has a dual affiliation with the Centre for Inflammation Biology and Cancer Immunology (CIBCI) at King’s College London https://www.kcl.ac.uk/lsm/research/divisions/diiid/centres/cibci. CIBCI is an interdisciplinary research centre with the mission to advance knowledge of the molecular and cellular mechanisms of inflammation and tumour immunology to further the understanding, diagnosis and treatment of inflammatory diseases and cancer. CIBCI research teams perform both fundamental and translational research on different aspects of inflammation biology and cancer immunology, including teams led by clinician scientists.