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Institute of Immunity and Transplantation

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Clare Bennett

Reader in Haemato-Immunology

Research area

DC and LC biology - DC immunotherapy.

Research programme

Research summary

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 macrohage 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.

Projects in the lab include:

1. Defining the plasticity and function of skin myeloid cells in GVHD

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.

Control of effector T cell function by LC

LC are born as tissue resident macrophages, but differentiate into cells that are functionally and transcriptionally similar to DC. One of our key challenges in our lab over many years has been to define the function of LC. We use models of bone marrow transplantation and GVHD to address this question. In collaboration with Ronjon Chakraverty in IIT we have demonstrated that conventional recipient DC populations are required to activated donor T cells, but that the function and survival of allo-reactive T cells is determined by the tissue in which they ultimately reside. In the skin epidermis, direct interaction with LC results in the programming of pathogenic T cells, which become resident within the skin. Thus different DC/LC populations interact with donor T cells at temporally and spatially distinct phases of the T cell response, and LC are required to license T cell function in situ in the epidermis. On-going work is aimed at defining the molecular nature of this interaction.

Defining repair of the LC network and restoration of immune homeostasis after immune injury

GVHD results in the killing of host allo-reactive cells in the skin, including LC. We are interested in understanding how immune homeostasis is re-established in the skin after GVHD, and the effect this has on cutaneous immune responses to infection and allergens.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. On-going work is aimed at defining how short-lived monocytes can become long-lived LC within the epidermal environment.

Immune injury due to GVHD also leads to long-term disruption of the dermal myeloid cell compartment. We are investigating how these changes impacts on pathology and immune function in the skin.

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.

Lentiviral vectors are potent vaccination vehicles, and we have show that this is partly due the direct- and cross-presentation of lentivirus-encoded antigens by DC.  Projects in the lab are aimed at understanding the cross-talk between DC and T cells in tumours and how this interaction changes in the context of adoptive T cell transfer of checkpoint blockade.  We also seek to target DC with lentivectors in combinatorial strategies to enhance T cell immunotherapy in poorly-responsive tumours.

Publications

Selected publications
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RPS Widget Placeholderhttps://research-reports.ucl.ac.uk/RPSDATA.SVC/pubs/CBENN26