of the PhD thesis project
laboratory combines experimental and computational approaches to study the
stroma-immune crosstalk, and aims to decipher the contribution of stromal
cells, especially cancer-associated fibroblasts (CAF), to regulating immune
responses against cancer. The preferential T cell retention in the peritumoral
stroma observed in a large fraction of lung tumors limits the success of
immunotherapies; dissecting the mechanisms regulating T cell exclusion is
therefore crucial to improve T cell-based therapies.
most recent therapeutic strategies have focused on immune cells, CAFs have been
underappreciated in cancer immunology. We previously reported that matrix
fibers in human NSCLC stroma form a dense physical barrier around tumor nests,
restricting lymphocyte: tumor cell contact. Here, the central hypothesis is
that CAF are key regulators of T cell migration, and that targeting CAF
molecules may enhance T cell infiltration in the tumor and synergize with
immunotherapy to induce tumor regression.
main objectives are:
characterize the CAF compartment in lung tumor lesions and unravel their role
in regulating T cell infiltration into the tumor mass,
key CAF molecules involved, and
the potential of targeting CAF molecules to promote T cell recruitment and
induce tumor regression.
data of CAF mapping from poorly and highly T cell-infiltrated lung mouse tumors
revealed candidate genes associated with lymphocyte infiltration. We will
cross-reference these signatures with single-cell RNAseq data we obtained from
human lung tumors to identify CAF-specific genes potentially mediating T cell
exclusion. We will test their effects on T cell dynamics and tumor lysis using
CRISPR to knockout the candidate genes in a novel tumor/CAF spheroid system we
recently developed. Finally, we will assess in vivo in mice the therapeutic
potential of treatments combining fibroblast-drug targets and checkpoint
interdisciplinary & intersectoral aspects of the project
Inter-disciplinarity: our research
project crosses the domains of biology, informatics, and pre-clinical research.
It combines both basic research, aiming to decipher mechanisms of the
fibroblast-immune cell crosstalk in tumor lesions, and translational research,
with the testing of CAF targets.
Intersectoral exposure: our lab has
strong collaborations with biotech companies (i.e. Shannon Turley from
Genentech; Takeda) for expertise, funding, and access to reagents and clinical
International dimension: international
co-mentors, USA: Ephraim Kenigsberg (Mount Sinai School of Medicine) for
computational analysis; Shannon Turley (Genentech) for stromal cell
biology/cancer immunotherapy. The thesis will involve conference meetings and a
visit to Mount Sinai, New York.
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Hashimoto D., Gnjatic S., Bhardwaj N., Palucka A.K., Brown B., Brody J.,
Ginhoux F., Merad M. Expansion and Activation of CD103+ Dendritic Cell
Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and
BRAF Inhibition. 2016. Immunity, 44(4):924-38.
3. Price J., Idoyaga J., Salmon H., Hogstad B., Bigarella C., Ghaffari S., Leboeuf M., Merad
M. CDKN1A regulates Langerhans cell survival and promotes Treg cell generation
upon exposure to ionizing irradiation. 2015. Nature Immunology, 16(10):1060-8.
4. Merad M., Salmon H. Cancer: a dendritic-cell brake on antitumor immunity.
2015. Nature, 523 (7560): 294-5. News and Views.
H., Franciszkiewicz K., Damotte D., Dieu-Nosjean MC., Validire P.,
Trautmann A., Mami-Chouaib F., Donnadieu E. Matrix architecture defines the
preferential localization and migration of T cells into the stroma of human
lung tumors. 2012. Journal of Clinical Investigation, 122(3):899-910.
The EuReCa Program is in english.For more information about the eligibility, please check the EuReCa webpage.