Description of the PhD thesis project
The focus of the group is to better understand the biology
of human antigen-presenting cells in health and pathology, in order to
manipulate the properties of these cells for disease treatment, especially in
In particular, we are interested in monocytes, which are
recruited by inflammtion and differentiate in tissues into monocyte-derived
macrophages (mo-Mac) and monocyte-derived dendritic cells (mo-DC). Mo-Mac are
known to suppress anti-tumor immune responses. Modulation of monocyte
differentiation has therefore emerged as a promising strategy for therapeutic
intervention. Using a novel model for human monocyte differentiation that we
have developped, we recently showed that mo-Mac and mo-DC represent two separate
lineages, controlled by distinct transcription factors (Goudot, Immunity 2017).
However, the regulatory circuitries of monocyte differentiation remain to be
The objective of the PhD project is to identify novel
molecular regulators governing monocyte fate commitment, and mo-DC versus
mo-Mac differentiation. To address these questions, we will analyse the
dynamics of monocyte differentiation using single-cell RNA-seq analysis and
reconstruct developmental trajectories using bioinformatics tools. To
complement this data, we will analyze chromatin accessibility and transcription
factor footprints using ATAC-seq. To test the role of newly identified
candidate regulators, we will either silence their expression in monocytes
using shRNA or inhibit their activity using drugs, and analyze monocyte
differentiation in our model. Finally, we will validate these findings using
tumor ascites samples from cancer patients, that contain naturally-occurring
human mo-DC and mo-Mac (Segura, Immunity 2013).
These results will
provide novel insight into the molecular ontogeny of mo-DC and mo-Mac, and will
be instrumental in the identification of potential molecular targets for the
therapeutic manipulation of monocyte differentiation.
International, interdisciplinary & intersectoral aspects of the project
The project involves concepts, tools and methods from
several disciplines (immunology, epigenetics, bio-informatics). In addition to
being supervised by E.Segura (an immunology expert), the PhD student will be
mentored by a bioinformatician to develop his/her skills in programming and
data analysis. In this project, the PhD student will therefore be trained both
in wet-lab techniques and in computational analysis.
The project will benefit from our established
international collaborations with single-cell RNA-seq analysis experts (Nir
Hacohen, Broad Institute).
Drugability of newly identified regulators will be
evaluated by our industrial partners. Pre-clinical tumor models are available
to carry out proof-of-concepts experiments.
1. Goudot C, Coillard A, Villani AC, Gueguen P, Cros A, Sarkizova S, Tang-Huau TL, Bohec M, Baulande S, Hacohen N, Amigorena S, Segura E. Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity. 2017, 47: 582-596.
2. Durand M and Segura E. The known unknowns of the human dendritic cell network. Front.
Immunol. 2015, 6:129
3. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R, Yona S. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny.
Nat Rev Immunol. 2014, 14(8):571
4. Segura E, Amigorena S. Inflammatory dendritic cells in mice and humans. Trends Immunol. 2013, 34(9):440
5. Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V, Amigorena A. Human inflammatory dendritic cells induce Th17 differentiation. Immunity. 2013, 38(2):336-48