Role of dendritic cells development in controlling the response to immune checkpoint inhibitors.
Position
A M2 internship position is available in the Guermonprez lab at Institut Pasteur Paris (“Dendritic cells and adaptive immunity” Unit, Immunology Department https://research.pasteur.fr/fr/department/immunology/) in collaboration with the Group of Julie Helft at Institut Cochin, UdPc (https://institutcochin.fr/equipes/phagocytes-immunologie-cancers)
Project
Cancer immunotherapy by immune checkpoints inhibitors (ICI, anti-PD1/PDL1 antibodies e.g.) represent a biomedical breakthrough bringing substantial therapeutics gain in patients. ICI act by reactivating exhausted T cells induced by the tumor. However, responsiveness to ICI immunotherapy is limited by the onset of therapeutic resistance.
Dendritic cells (DCs) are the sentinel of the immune system. When properly activated, DCs can lead to the activation and expansion of anti-tumoral T cell responses which are essential for therapeutic success. DCs are developmentally and functionally heterogeneous and encompass multiple subsets including XCR1+ DCs, and a variety of IRF4+ DCs (DC2As, DC2Bs, DC3s) and plasmacytoid DCs. DCs are short-lived cells continuously developing from hematopoietic stem cells in the bone marrow. Our work has already identified that successful ICI treatment of tumor-bearing mice leads to the appearance of a novel early hematopoietic DC-progenitors in the bone marrow. We therefore hypothesize that successful immunotherapy depends on the development of anti-tumor DC subsets. The general objectives of this project are:
- To further characterize the dynamics of DCs populations in tumors and draining lymph nodes and to determine the functional contribution of DCs subsets to the response to ICI immunotherapy.
- To identify the developmental mechanisms controlling the dynamics of DC generation during response or resistance to ICI immunotherapy.
- To evaluate novel interventions counteracting ICI resistance at the DC development level.
This project will be developed in the context of preclinical murine model of melanoma responsive or not to ICI.
Specific objectives and methods
The specific objectives of the M2 are:
1°) To identify which DC population undergo dynamic changes during ICI immunotherapy. Tumors and tumor draining lymph nodes will be analyzed by spectral flow cytometry and single cell RNAseq. The functional contribution of DCs subsets will be tested by performing ICI immunotherapy in DC-deficient genetically engineered mice (Xcr1DTA, pDCDTA, pDC-likeDTR).
2°) To determine the developmental potential of ICI-induced hematopoietic progenitors in the bone marrow and better understand their lineage relationship with ICI-regulated DCs in periphery. This will be achieved by FACS based cell sorting, culture assays and adoptive transfer in recipient mice.
3°) To evaluate novel immunotherapies purposed to rewire hematopoïesis for the generation of DCs. These interventions will be evaluated for their ability to counteract resistance to ICI. To this end, we will attempt at inducing the generation of DC-progenitors supporting the response to ICI by delivering hematopoietic growth factors in ICI-resistant tumor models.
Profile
We are looking for highly motivated individuals considering pursuing their M2 with a PhD.
The candidate is expected to have:
- A keen interest for developmental immunology, cancer immunology and immunotherapy.
- Motivation to work with pre-clinical, murine model of cancer and immunotherapy (animal experimentation).
- English speaking and ability to work in a cooperative, multi-cultural and multi-disciplinary environment.
- Dynamism, self-organization, autonomy and drive.
Interest for computing biology (R programming, image analysis) will be an additional asset.
Contact & applications:
Applications should be sent to pierre.guermonprez@pasteur.fr; julie.helft@inserm.fr
“Dendritic cells and adaptive immunity” Unit, Immunology Department, Institut Pasteur.
For applications, please provide: 1 CV, the email contact for 2 references.