Dendritic Cell Immunotherapy
We explore the development and function of Langerhans Cell (LC) and Dendritic Cell (DC) within the skin and how these processes become dysregulated in cancer and as a result of immune pathology.
Our research
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.
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.
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.
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.
Resurrecting sentinels in the skin
A research team led by Dr Clare Bennett has shown how damaged Langerhans cells in the skin can be replenished by monocytes in order to preserve essential immune function.
28 August 2019
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 ... Bennett CL. Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity. Sci Immunol. 2024 Sep 6;9(99): eadp0344.
Bennett CL, Perona-Wright G. Metabolic adaption of mucosal macrophages: Is metabolism a driver of persistence across tissues? Mucosal Immunol. 2023 Oct;16(5): 753-763.
Howell R, Davies J, Clarke MA ... Bennett CL. Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling. Sci Adv. 2023 Apr 14;9(15): eadd1992.
West HC, Davies J, Henderson S ... Bennett CL. Loss of T cell tolerance in the skin following immunopathology is linked to failed restoration of the dermal niche by recruited macrophages. Cell Rep. 2022 May 17;39(7): 110819.
Dertschnig S, Evans P, Santos E Sousa P ... Bennett CL, Chakraverty R. Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity. J Clin Invest. 2020 Apr 1;130(4): 1896-1911.
Ferrer IR, West HC, Henderson S ... Bennett CL. A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury. Sci Immunol. 2019 Aug 23;4(38): eaax8704.
Santos E Sousa P, Ciré S, Conlan T ... Bennett CL, Chakraverty R. Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease. JCI Insight. 2018 Mar 8;3(5): e97011.
Hotblack A, Holler A, Piapi A, Ward S, Stauss HJ, Bennett CL. Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR-Engineered T Cells in Melanoma. Mol Ther. 2018 Jun 6;26(6): 1471-1481.
Galleu A, Riffo-Vasquez Y, Trento C ... Bennett C, Dazzi F. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med. 2017 Nov 15;9(416): eaam7828.
Funders
Contact
434C Paul O'Gorman Building
72 Huntley Street
London, WC1E 6DD
