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Selective contributions of NF-B subunits to regulatory T cell biology
Abstract
Cancers use a wide variety of mechanisms to dampen tumor immune response. Among them,
CD4+Foxp3+ regulatory T cells (Tregs) are largely described to inhibit the function of effector cells.
Therefore, precisely understanding the mechanisms governing Treg homeostasis may be a
valuable strategy to enhance immune responses against cancer. It is established that
transcription factor NF-B plays a major role in Treg development; we are now analyzing the role
of canonical p65 and c-Rel NF-B subunits in mature Tregs.
We found that specific ablation of one or both NF-B subunits in Tregs drove a gradual
autoimmune syndrome. This was associated with profound changes in the molecular signature of
NF-B deficient Tregs, which down-regulated Treg-associated genes while acquiring an effectorlike phenotype. Mechanistically, ChIP-Seq analyses showed that Foxp3 and NF-kB cooperated
to establish a lineage-specific transcriptome. We next explored the role of NF-B in Treg
homeostasis during tumor growth. Strikingly, melanoma growth was drastically reduced in mice
lacking c-Rel, but not p65, in Tregs. This was associated with an increased effector T cell
activation. Moreover, chemical inhibition of c-Rel delayed melanoma growth and potentiated antiPD-1 checkpoint-blockade therapy by impairing the Treg transcriptional program.
Our data demonstrate a specific role for each NF-B subunit in Treg function and homeostasis,
and highlights a new therapeutic opportunity for the treatment of cancer.
Personal statement
My long-term objective in research is to explore the cellular and molecular mechanisms driving
immune responses and immunological tolerance and their relevance in animal models and human
diseases. My academic training in Paris allowed me to have a general overview of multiple fields
of biology and health sciences, in particular immunology. I achieved my PhD thesis, as well as a
short postdoc, under the supervision of Benoit Salomon and Eliane Piaggio, in the laboratory of
David Klatzmann, at the Pitie-Salpetriere Hospital in Paris. My thesis work was focused on the
study of the homeostasis of Foxp3+ regulatory T cells (Treg) during autoimmune diabetes and
EAE, a murine model for MS. I sought to further explore the molecular mechanisms driving T-cell
functions, and by doing so, to enhance my knowledge in the field of molecular immunology. I
joined the laboratory of Sankar Ghosh in New York, Chairman of Department of Microbiology and
Immunology at Columbia University, New York. The lab is renowned for its expertise in the NFB family of transcription factors. We have generated mice carrying conditional deletions of NFB subunits either in total T cells or specifically in Treg. These innovative models allowed me to
decipher the respective roles of each NF-B subunit in the effector and regulatory mechanisms
involved in autoimmunity and cancer.
After 5 years in New York, I want to further advance in my academic career and look for a new
host laboratory in France. I believe that my background may serve as a base for further studies
in a new laboratory. I wish to join a dynamic and renowned institution in order to continue my
work on the role of NF-B and other signaling pathways in T-cell biology, in particular Treg, during
autoimmune and anti-tumor responses.