| Research
Group |
 |
| Curriculum
Vitae |
|
Frédéric
Lévy graduated from the ETH Zurich in 1987 and obtained his doctorate
from the Karolinska Institute in Stockholm, Sweden in 1992. During a postdoctoral
stay in the lab of Prof. A. Varshavsky at the California Institute of
Technology in Pasadena, California, he worked on biochemical aspects of
the ubiquitin-proteasome degradation pathway in yeast and mammalian cells.
In 1996, he moved to the Ludwig Institute in Lausanne, Switzerland. In
1999, he received the “Junior Investigator Award” of the Cancer
Research Institute (New York) and was elected “Professeur boursier
FNS” in 2000. He was promoted to Associate Member of the Ludwig
Institute in 2003 and Associate Professor ad personam of the University
of Lausanne in 2006. In 2004, he shared the “Leenards Prize”
with Prof. V. Piguet.
| Research
Interests |
|
1.
Factors affecting the efficacy of cancer vaccines in vivo
Antigen
processing - Antigen processing plays an important role not only in the
recognition of tumor cells by T cells but also in the activation of anti-tumor
T cells. We have demonstrated that the expression of immunoproteasome,
a type of proteasome that is constitutively expressed in dendritic cells
and in melanoma cells exposed to interferon -γ, prevented the efficient
production of several MHC class I-restricted peptide tumor antigens, including
the melanoma-associated peptide Melan-A26-35 (1). More recently,
we have shown that the constitutive expression of immunoproteasome in
dendritic cells also limited the efficient activation of anti-Melan-A
T cells in vivo (2). Inversely, some peptide tumor antigens are more efficiently
produced by immunoproteasome (3). We are currently studying the immunological
impact of this latter phenomenon in vivo.
Lentivector-based
vaccines - Based on the UPR technology developed earlier (4), we have
produced lentivector vaccines incorporating the sequence of EGFP-Ubiquitin
fused to various peptide tumor antigens. Administration of these vaccines
to mice leads to potent CD8+ T-cell responses, detectable ex vivo (5,
6). We are currently developing new lentivectors with targeted gene expression
to induce more specific immune responses.
B-cell
and CD4+ T-cell responses - Induction of effective CD8+
T-cell responses requires CD4+ T-cell help. We have recently
found that lentivector-based vaccines not only elicited tumor antigen-specific
CD4+ and CD8+ T cells but also stimulated B-cell responses
against tumor antigens (Garcia et al., submitted). The impact of the B-cell
response on the cellular immune response is currently under investigation.
CD8+
T-cell memory - We have shown that a single immunization of mice with
lentivector-based vaccines elicited longer lasting CD8+ T-cell responses
than conventional vaccines (6). Memory T cells remained detectable ex
vivo for over 4 months after a single injection. Using this system, we
are investigating the mechanism by which recombinant lentivectors induce
higher frequencies of memory T cells.
Vaccine-induced
immune response against melanoma - N-RasQ61K INK4a+/- mice develop spontaneous
melanoma with high incidence after approximately 11 months. However, topical
treatments of the skin with carcinogens induce metastatic melanoma within
3 months. We are using these mice to test the in vivo effect of our lentivector-based
vaccines in preventing tumor appearance (prophylactic vaccine) or blocking
tumor growth (therapeutic vaccine). This model will also be used to study
the interplay between tumor cells and anti-tumor T cells.
2.
Analysis of gene expression in normal colon and colon carcinoma by massively
parallel signature sequencing (in collaboration with the group of V. Jongeneel)
We
have analyzed the expression of several cancer/testis antigens in primary
and metastatic colorectal cancer samples of over 40 patients and shown
that most are expressed at frequencies lower than 15% (7). We have also
performed a comprehensive analysis of genes that are differentially expressed
in normal colon epithelia and colon carcinomas using the recently developed
technique coined MPSS (Massively Parallel Signature Sequencing) (8). We
have found that the expression of many genes is deregulated in colon carcinomas.
Interestingly, we found that the transcription of a member of the endogenous
retroviral elements (HERV-H) is selectively activated in a proportion
of primary and metastatic colon carcinomas. We are currently evaluating
this and several other gene products with the aim of identifying new targets
for T-cell vaccines.
3.
Regulation of melanoma-associated proteins by ubiquitin-mediated degradation
The
melanoma-associated protein Melan-A accumulates in melanosomes. Melanosomes
are intracellular organelles involved in the production of the pigment
melanin. Even though a fraction of Melan-A is degraded by the proteasome,
the bulk of Melan-A is degraded by the lysosome. This process requires
prior ubiquitylation. We have identified and characterized two ubiquitin
ligases, AIP4/Itch and NEDD4, that are responsible for ubiquitylating
and targeting Melan-A to lysosomes (9). More recently, we have identified
several proteins that specifically interact with Itch in human melanoma
cells. Interestingly, one of these proteins is involved in intracellular
organelle transport and its function in melanosome trafficking is currently
analyzed. Other interacting proteins are also under investigation.
| Selected
publications |
|
1. Morel, S. et al.
(2000) Immunity
12, 107-117.
2. Chapatte, L. et al. (2006) Cancer
Res. 66, 5461-5468.
3. Schultz, E. S. et al. (2002) J.
Exp. Med. 195, 391-399.
4. Valmori, D. et al. (1999) J.
Exp. Med. 189, 895-905.
5. Esslinger, C. et al. (2003)
J. Clin. Invest. 111, 1673-1681.
6. Chapatte, L. et al. (2006) Cancer
Res. 66, 1155-1160.
7. Alves, P.M. et al (2007) Cancer
Immunol. Immunother. 56, 839-847.
8. Brenner, S. et al. (2000) Nat.
Biotechnol. 18, 630-634.
9. Lévy, F. et al. (2005) Mol.
Biol. Cell 16, 1777-1787.
Complete
publication list (PDF) |
