DC cancer · Development and immunological control of dendritic cell cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-05-01 → 2017-04-30
- EU contribution
- €183,455
- Participants
- 2
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Development and immunological control of dendritic cell cancer
Dendritic cells (DCs) are powerful cells of the innate immune system that are central to immunity against infection and cancer. This prominent role of DCs in the initiation of immune responses has led to the hypothesis that the immunological potential of DCs hinders DC cancer development. Diagnosis of DC cancer in humans is complicated by the fact that histiocytosis – defined as a hyperplasia of APC like DC or macrophages - can be a consequence of immunological rather than neoplastic transformation. Recent reports suggest that DC cancer can indeed form in humans and account for some of the histiocytic malignancies observed in the clinic. However, the steps that occur during DC cancer development have not been studied so far, due to the lack of appropriate models. We thus generated a novel, genetically engineered cancer model resulting in spontaneous neoplastic transformation in cells of the DC lineage in mice. These Clec9a Kras-G12D mice allowed us to characterise DC cancer formation and study the immunological consequences of neoplastic transformation of DCs and DC precursors. Our work establishes that oncogenic transformation of DCs leads to rapid development of DC cancer in multiple organs with 100% penetrance. This development of DC cancer could be induced by a small number of cells and was not prevented in the presence of untransformed DCs. Furthermore, DC cancer developed despite a lack of overt immune function and transformed DCs could be sufficiently activated upon stimulation. Importantly, DC cancer cells were immunogenic upon transplantation into immune competent mice despite their ability to grow unabated in the original host, thus indicating that immunological control of DC cancer is in principle possible but does not occur during its spontaneous generation. In summary, our data provide a detailed characterisation of DC cancer development and immunological properties of transformed DCs. DC precursors, if transformed, can give rise to haematological malignancy in mice, raising the question of whether this might also occur in some circumstances in humans and might be the underlying cause of certain histiocytic pathologies observed in human patients.
Data: CORDIS, © European Union
Project objective
Dendritic cells (DC) are powerful antigen-presenting cells that can induce antigen-specific adaptive immunity to pathogens but also protective immunity against transformed self, i.e. cancer. This crucial role of DC makes them an attractive target in cancer vaccination. However, DC can also negatively regulate immunity by inducing antigen-specific tolerance and are a target in immunomodulatory approaches aimed at dampening autoimmunity or allergy. Given this dual role in immunity and tolerance it is hard to predict what would happen if DC were to become neoplastically transformed. Their immunogenic potential could make transformed DC highly susceptible to control by the immune system, which might explain why DC cancers are rarely observed in humans. In contrast, their tolerogenic potential could make transformed DC especially adept at escaping immunological control. So far, the aetiology of DC cancer and its immunological consequences remain elusive due to the lack of appropriate models to study the disease. In order to investigate the feasibility of DC tumour formation and the immune control of DC tumours, a novel genetically-engineered mouse model of DC cancer has been generated. We will use this model to characterise DC tumour development in vivo and establish which DC subsets contribute to DC cancer. Furthermore, we will adapt this model so that we can control the location and onset of neoplastic transformation of DC in vivo. Both models will then be employed to investigate to which extent DC cancer is recognised and modulated by cells of the immune system. Furthermore, we will assess whether transformed DC exploit tolerogenic mechanisms to progress into tumours. Our proposal will give novel insights into the biology of cancer development and its control by the immune system. We anticipate that understanding these processes will provide important insights into immune surveillance and the role of DC in anti-cancer immunity, helping to improve cancer immunotherapy.
Original text from CORDIS.
Participants
- THE FRANCIS CRICK INSTITUTE LIMITED · LondonCoordinatorUnited Kingdom
- CANCER RESEARCH UK LBG · LONDONUnited Kingdom
Links
Data: CORDIS, © European Union