Close
Group Leader: Professor Clare Bennett
Dendritic cells (DC) are specialised immune cells that link innate and adaptive immunity. In the skin they function in co-operation with other immune cells, including Langerhans cells (LC), the unique macrophage population of the epidermis, and other myeloid and lymphoid populations in the dermis. Together these cells work together to maintain skin immune homeostasis.
Our key research goals are to gain a greater understanding of LC and DC development and function within the skin, and how these processes become dysregulated in cancer and as a result of immune pathology. We use this knowledge to develop new ways of harnessing DC for immunotherapy.
Research focus
1. Defining the plasticity and function of skin myeloid cells in health and disease.
DC have the potential to activate immune responses against tumours. However, in other settings DC may also drive unwanted immune responses, resulting in immunopathology and tissue damage. This dichotomy is particularly relevant after bone marrow transplant when DC likely drive the anti-tumour response, but also activate donor T cells to destroy tissues such as the skin and intestine (graft-versus-host disease, GVHD). We are interested in understanding how skin DC drive cutaneous immunopathology, and in turn, how damage to the skin alters the resident DC and LC populations.
- Redefining the Langerhans cell paradigm
LC are a unique population of DC-like macrophages that form a network throughout the outer epidermal layer of the skin. This localisation and their function as antigen presenting cells had led to the paradigm that LC were the primary immune cells responsible for activating T cell immunity to skin infections. But studies by our lab and others have suggested that other DC in the skin may be more important in this role, leading us to question what the primary function of LC is? To address this question we use models of LC replacement to determine the tissue-specific signals that shape the LC network. We have shown that immune injury leads to replacement of the resident LC network by monocyte-derived cells that became functionally and transcriptionally indistinguishable from the cells they replace. We are focused on addressing fundamental questions about the intrinsic and extrinsic signals that control monocyte differentiation in the epidermis, and what the consequence of LC replacement is for the immune and non-immune functions of LC in the skin.
- What are the long-term impacts skin graft-versus-host disease on the skin immune network?
The balance of immune cells is established in the skin around birth. We are interested in investigating how diseases like GVHD upset this balance and whether it can be re-set in adult skin. Our work has suggested that disease leaves a “scar” in the skin such that macrophages remain activated long after the GVHD is resolved. This may have important impacts on other immune responses in the skin, especially control of unwanted immune responses to allergens.
2. Harnessing DC for cancer immunotherapy
The development of T cell immunotherapies has revolutionised our approach to treating cancer. However, despite this many patients and cancers do not respond, and there is a need to build on this success to improved treatment outcomes. DC are essential for T cell-mediated rejection of tumours, but we still know little about how DC may work with T cells to promote tumour destruction after immunotherapy. We have a number of projects in the lab that are seeking to apply our understanding of DC biology to improving immunotherapeutic treatments of across cancers.
In collaboration with Professor Fisher’s lab at UCL we are also seeking to apply our understanding of LC and DC biology to computational models of melanoma treatment and resistance to immune checkpoint inhibition.
Group members
- Anna Appios (BBSRC post-doc)
- Inȇs Carvalho (CRUK post-doc)
- Sara Seshadri (Autolus-funded PhD)
- Francesco Moscato (BBSRC LIDo DTP PhD)
- Charlotte Galley (Percy Stevens fellow PhD)
- Rosie Amerikanou (CRUK CoL PhD led by Prof. Adele Fielding)
Selected Publications
Appios A, Davies J, Sirvent S, Henderson S, Trzebanski S, Schroth J, Law ML, Carvalho IB, Pinto MM, Carvalho C, Kan HY, Lovlekar S, Major C, Vallejo A, Hall NJ, Ardern-Jones M, Liu Z, Ginhoux F, Henson SM, Gentek R, Emmerson E, Jung S, Polak ME, Bennett CL. Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity. Sci Immunol. 2024 Sep 6;9(99):eadp0344. doi: 10.1126/sciimmunol.adp0344. Epub 2024 Sep 6.
Clare L. Bennett and Georgia Perona-Wright. Metabolic Adaption of Mucosal Macrophages: Is Metabolism a Driver of Persistence Across Tissues? (2023). Mucosal Immunology. doi: 10.1016/j.mucimm.2023.06.006.
Rowan Howell, James Davies, Matthew A Clarke, Anna Appios, Inȇs Mesquita, Yashoda Jayal, Ben Ringham-Terry, Isabel Boned Del Rio, Jasmin Fisher* and Clare L. Bennett*. Localized immune surveillance of primary melanoma in the skin deciphered through executable modelling. (2023) Science Advances 9(15):eadd1992. doi: 10.1126/sciadv.add1992.
Heather C. West, James Davies, Stephen Henderson, Sophie Ward, Ivana R. Ferrer, Chanidapa A. Tye, Andres Vallejo, Laura Jardine, Matthew Collin, Marta E. Polak and Clare L. Bennett. Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages. (2022) Cell Reports 39(7):110819. doi: 10.1016/j.celrep.2022.110819.
Dertschnig, S., Evans, P., Santos E Sousa, P., Manzo, T., Ferrer, I.R., Stauss, H.J., Bennett, C.L., Chakraverty, R. (2020). Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity. J Clin. Invest. doi:10.1172/JCI133102
Ivana R. Ferrer, Heather C. West, Stephen Henderson, Dmitry S. Ushakov, Pedro Santos e Sousa, Jessica Strid, Ronjon Chakraverty, Andrew J. Yates and Clare L. Bennett. A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury. (2019) Science Immunology doi: 10.1126/sciimmunol.aax8704.
Santos e Sousa, Severine Cire, Thomas Conlan, Laura Jardine, Claire Winship, Ivana R. Ferrer, Cara Lomas, Sophie Ward, Heather West, Simone Dertshnig, Sven Blobner, Terry K. Means, Stephen Henderson, Daniel H Kaplan, Matthew Colllin, Vincent Plagnol*, Clare L. Bennett* and Ronjon Chakraverty*. Peripheral tissues re-program CD8+ T cells for pathogenicity during graft-versus-host disease. (2018) J Clin. Invest. Insight. 3(5). pii: 97011/jci.insight.97011.*Co-senior authors, CLB and RC are co-corresponding authors.
Alastair Hotblack, Angelika Holler, Alice Piapi, Sophie Ward, Hans J Stauss* and Clare L. Bennett*. Tumour-resident dendritic cells and macrophages modulate the accumulation of TCR-engineered T cells in melanoma. (2018) Mol. Therapy. 26: 1471-1481.
Antonio Galleu, Yanira Riffo-Vasquez, Cristina Trento, Cara Lomas, Luigi Dolcetti, Krishma Halai, Tik S. Cheung, Sophie Ward, Malte von Bonin, Ronjon Chakraverty, Ling Weng, Giovanna Lombardi, Fiona M. Watt, Kim Orchard, David I. Marks, Jane Apperley, Martin Bornhauser, Henning Walczak, Clare L. Bennett and Francesco Dazzi. Perforin-dependent apoptosis in mesenchymal stromal cells is required to initiate host-mediated in vivo immunomodulation in graft-versus-host disease. (2017) Science Transl. Med. doi: 10.1126/scitranslmed.aam7828
Funders
- BBSRC
- Cancer Research UK
- Percy Stevens Scholarship