Translational Tumor Immunology Group

It is now well established that cancer patients may acquire tumor specific T- and B-cell immunity. Various types of human tumor cells often express multiple CTL-defined tumor antigens that are shared among tumors, providing the rationale for generic vaccines applicable to large subsets of cancer patients. Our main interests are in understanding the dynamics of tumor antigen-specific T cell responses and applying this knowledge to the design of peptide-based therapeutic vaccines.

Monitoring antigen-specific CTL and helper T cell responses.

Recently, we adopted the fluorescent tetramer technology to visualize antigen-specific cells directly by flow cytometry. We have enumerated and functionally characterized single tumor antigen specific T cells in blood, metastatic nodes and tumor masses from patients with metastatic melanoma as well as in blood from healthy individuals. We identified a particularly abundant T cell repertoire specific for the HLA-A2/Melan-A/MART-1 antigen, expressed in normal melanocytes and melanoma cells, that is directly accessible to analysis by tetramers. High frequencies of these T cells are detectable in single CD8+ human thymocytes, in cord blood and the majority of HLA-A2 healthy individuals. These T cells remain in a naïve functional state of differentiation and undergo limited expansion in the periphery. A fraction of this repertoire is activated in patients with melanoma and memory type T cells accumulate at relatively high frequencies in metastatic lesions. We are currently determining the functional potential of antigen-specific T cells freshly recovered from tumors. We are also interested in setting up models to understand the molecular mechanisms underlying the thymic selection of high numbers of Melan-A/MART-1 tetramer+ lymphocytes. Efficient induction of anti-tumor immunity requires the participation of helper T cells. Numerous MHC class II-restricted tumor antigens have been recently identified mainly in melanoma. We have recently started a project to use MHC class II tetramers for the visualization of helper antigen specific T cells in melanoma. We are using well defined mouse models, including an OT-II x eGFP-Foxp3 mouse line to address the role of antigen specific CD8 T cell effector to CD4 Treg ratio in the quality of the anti-tumor CD8 T cell response and how vaccine formulation, type of adjuvants, can modulate this ratio.

Adoptive transfer immunotherapy of cancer.

Experimental evidence in mouse models clearly show potent anti-tumor activity of adoptively transferred CTL. Recent trials have also shown that antigen-specific CD8 T cells can be safely transferred in humans but clinical efficacy remains limited. We have started a project aiming at using retroviral TCR gene transfer for adoptive transfer of autologous T cells redirected to the tumor antigen Melan-A/MART-1 in melanoma patients. Currently, we are optimizing in vitro expansion protocols and making the preparations for a first clinical trial in collaboration with the Service of Oncology of the Lausanne University Hospital (O. Michielin, S. Leyvraz) and the Netherlands Cancer Institute (J. Haanen, T. N. Schumacher).

HLA-A2 transgenic mouse models for preclinical testing of cancer vaccines.

The most frequently expressed MHC class I allele in various ethnic groups is HLA-A2. Transgenic mice carrying this allele lend themselves to preclinical testing of peptide vaccines. We have recently found that HLA-A2 tetramers can be used to monitor the anti-peptide CTL response to vaccination in mouse blood, lymph nodes and spleen. Using this system we observed that a combination of incomplete Freund's adjuvant and synthetic oligodeoxynucleotides containing CpG motifs synergize in the induction of a strong Melan-A/MART-1 peptide specific CTL response. We are generating Melan-A/MART-1 knock out mice in the HLA-A2 transgenic background to study the influence of central tolerance in the repertoire of Melan-A/MART-1 specific T cells. Recently, we are focusing on the role of various TLR agonists in modulating the strength and the quality of the elicited T cell response. To model the improvement of anti-tumor clinical efficacy of subunit vaccines, we are also interested in combinations of synthetic vaccines with immune checkpoint blockade, immunomodulatory compounds, chemotherapy and/or radiotherapy.
 

Harnessing NKT cells for cancer immunotherapy.

Soluble constructs of CD1d presenting the superagonist alpha-galactosyl-ceramide have been developed (A. Donda, J-P Mach) which are promising as agents to activate NKT cells in vivo with minimal subsequent anergy. Moreover, these constructs are being targeted to the tumor site by addition of the recognition domains of selected antibodies such as anti-CEA and anti-HER-2.
 

Molecular mechanisms underlying CD8 T cell differentiation.

We are interested in understanding the molecular pathways involved in imparting effector cell differentiation or memory T cell formation. An ongoing project examines the role of miR 155 in the initial expansion of CD8 T cells following in vivo engagement of antigen in a model of LCMV, wild type, acute infection and also in one of synthetic peptide vaccination. Initial results suggest that miR 155 is essential for optimal CD8 T cell expansion and survival and acts in a cell autonomous manner. Future studies will examine the role of this and other selected miRNAs in memory formation and identify their molecular targets in CD8 T cells.

Phase I clinical trials of peptide vaccination in melanoma.

Quantitative monitoring of vaccine-induced tumor-specific CTL responses is a major focus in our vaccination program. In collaboration with Daniel E. Speiser and clinicians at the Multidisciplinary Oncology Center, University Hospital of Lausanne (CHUV) we design and perform clinical trials in appropriately selected patients with metastatic melanoma (see D.E. Speiser's web page).
 

Bron, L., Jandus, C., Andrejevic-Blant, S., Speiser, D. E., Monnier, P., Romero, P. and Rivals, J.-P. 2012. Prognostic value of arginase-II expression and regulatory T cell infiltration in head and neck squamous cell carcinoma. Int. J. Cancer (EPub ahead of print)

Castro-Díaz, N., Salaun, B., Perret, R., Sierro, S., Romero, J.F., Fernández, J.A., Rubio-Moraga, A., Romero, P. 2012. Saponins from the Spanish saffron Crocus sativus are efficient adjuvants for protein-based vaccines. Vaccine 30: 388-97

Guarda. G., Braun, M., Staehli, F., Tardivel, A., Mattmann, C., Förster, I., Farlik, M., Decker, T., Du Pasquier, R.A., Romero, P., Tschopp, J. 2011. Type I IFN inhibits IL-1 production and inflammasome activation. Immunity.

Salaun, B., Zitvogel, L., Asseliln-Paturel, C., Morel, Y., Chemin, K., Dubois, C., Massacrier, C., Conforti, R., Chenard, M.P., Sabourin, J.C., Goubar, A., Lebecque, S., Pierres, M., Rimoldi, D., Romero, P., André, P. 2011. TLR3 as a biomarker for the therapeutic success of double stranded RNA in breast cancer. Cancer Research

Cesson, V., Rivals, J.P., Escher, A., Piotet, E., Thielemans, K., Posevitz, V., Dojcinovic, D., Monnier, P., Speiser, D.E., Bron, L., Romero. P. 2010. MAGE-3 and MAGE-4 specific CD4+ T cells in Head and Neck cancer patients: detection of naturally acquired response and identification of new epitopes. Cancer Immunol Immunother. 2010 Sep 21.

Jandus, C., Bioley, G., Dojcinovic, D., Derré, L., Baitsch, L., Wieckowski, S., Rufer, N., Kwok, W.W., Tiercy, J.M., Luescher, I.F., Speiser, D.E., Romero, P. 2009. Tumor antigen specific FOXP3+ CD4 T-cells identified in human metastatic melanoma: peptide vaccination results in selective expansion of Th1-like counterparts. Cancer Res. 69:8085-93

Speiser, D.E., Baumgartner, P., Voelter, V., Devevre, E., Barbey, C., Rufer, N., and Romero, P. 2008. Unmodified self antigen triggers human CD8 T-cells with stronger tumor reactivity than altered antigen. PNAS (USA) 11;105(10):3849-54

Salaun, B., Lebecque, S.,, Sampsa Matikainen, S.,, Rimoldi, D., and Romero, P. 2007 Toll-like Receptor 3 expressed by melanoma cells as a target for therapy? Clinical Cancer Research 13:4565-74

Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N. 2007. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes.J Immunol. 178:4112-9

Tabiasco, J., E. Devevre, N. Rufer, B. Salaun, J.-C. Cerottini, D.E. Speiser and P. Romero. 2006. Human effector CD8+ T lymphocytes express toll like receptor-3 as a functional coreceptor. J. Immunol. 177:8708-13

Bioley, G., C. Jandus, S. Tuyaerts, D. Rimoldi, W.W. Kwok, D.E. Speiser, J.M. Tiercy, K. Thielmans, J.-C. Cerottini and P. Romero. 2006. Melan-A/MART-1-specific CD4 T cells in melanoma patients: identification of new epitopes and ex vivo visualization of specific T ells by MHC class II tetramers. J. Immunology. 177:6769-79

Devêvre, E., Romero, P., Mahnke, Y. 2006 LiveCount assay: concomitant measurement of cytolytic activity and phenotypic characterization of CD8+ T cells by flow cytometry. J. Immunol. Methods:311:31-46

Appay V., D.E. Speiser, N. Rufer, S. Reynard, C. Barbey, J.-C. Cerottini, S. Leyvraz, C. Pinilla and P. Romero. 2006. Decreased specific CD8+ T cell cross-reactivity of antigen recognition following vaccination with Melan-A peptide. Eur.J.Immunol 36: 1805-1814

Pittet, M.J., Gati, A., Le Gal, F.A., Bioley, G., Guillaume, P., de Smedt, M., Plum, J., Speiser, D.E., Cerottini, J.-C., Dietrich, P.Y., Romero, P., Zippelius, A. 2006 Ex vivo characterization of allo-MHC-restricted T cells specific for a single MHC/peptide complex. J.Immunol. 176: 2330-2336

Alena Donda, Research Associate

Jan Dudda, Postdoctoral fellow
Camilla Jandus, Postdoctoral fellow 
Godehard Scholz, Postdoctoral fellow
Lianjun Zhang, Postdoctoral fellow

Natália Botehlo, PhD student
Stéphanie Corgnac, PhD student
Gwennaëlle Monnot, PhD student

Donata Rimoldi, Associate Investigator
Katja Mühlethaler, Research Assistant

Martine Van Overloop, Secretary

Faiza Mourali, Technical Assistant