 Nicolas Larmonier, PhD
Contact Information:
Education:
- University of Burgundy, 2004
Research:
Immunity against tumors depends on complex innate and adaptive immune responses that involve the sequential mobilization of ‘messenger’ and ‘killer’ immune cells. However, despite the arsenal harbored by the immune system to ensure tumor immunosurveillance, cancers can escape immune detection and elimination. Our laboratory conducts a basic and translational research program aimed at advancing new immunotherapeutic strategies as a cure for cancer. We are specifically focusing on deciphering the phenomena of tumor-induced immunosuppression and are investigating approaches to override their negative impact on antitumoral immunity. A concomitant and complementary area of research centers on the optimization and development of cancer vaccines and on the identification of novel cellular actors of the immune system that may be manipulated to control malignancies. This two-step strategy converges toward the promotion of tightly orchestrated tumor-specific immune responses. The primary research areas in our laboratory are the following:
1) Mechanisms of tumor-induced immunosuppression
- Role and modulation of regulatory T cells (Treg) in cancer.
One subset of T cells, called CD4+CD25+FoxP3+ regulatory T lymphocytes (Treg) critically contribute to the complex regulatory networks that govern induction and persistence of tumor-mediated immune tolerance. Regulatory T cells induced by growing tumors compromise the activity of anti-tumor effector CD8+ and CD4+ T cell and restrain the function of dendritic cells, therefore representing an obstacle for successful immunotherapy. We have demonstrated that imatinib mesylate (Gleevec, a specific tyrosine kinase inhibitor) can negatively modulate the suppressive activity of Treg in vitro and in vivo by interfering with activation signals relayed by the T cell receptor. We have further established that imatinib can be efficiently associated with anti-tumoral vaccines such as tumor antigen-loaded dendritic cells or a tumor-derived chaperone-rich cell lysate vaccine (CRCL) developed in our laboratory to treat established and metastatic tumors. Ongoing investigations are evaluating the influence of imatinib on the conversion of CD4+CD25-FoxP3- T cells into FoxP3+ Treg in vitro and in tumor-bearing animals.
We are exploring additional therapeutic approaches to eliminate or inactivate tumor-induced Treg and are pursuing the study of the mechanisms leading to the induction and regulation of their immunosuppressive function.
- Myeloid-Derived Suppressor cells in cancer.
Myeloid-derived suppressor cells (MDSC) contribute to tumor-induced immunosuppression. The number of these cells is increased in tumor-bearing hosts and they may specifically or non- specifically suppress immunity by mechanisms involving arginase-1, reactive oxygen and nitrogen species. In mice MDSC express the CD11b and Gr-1 markers and may be involved in the generation of Treg. We have initiated a project aimed at evaluating the role and modality of induction of these cells in cancer and at exploring the reciprocal interaction between tumor-induced MDSC and Treg.
2) Promotion of anti-tumor immunity
- Development, optimization and translation to humans of a Chaperone Rich Cell Lysate vaccine (CRCL).
We have developed a novel method that efficiently enriches for multiple chaperone complexes from tumor lysates using free solution isoelectric focusing (FS-IEF). We have documented in numerous animal tumor models that this Chaperone Rich Cell Lysate (CRCL) or dendritic cells (DC) loaded with tumor-derived CRCL represent efficient anti-cancer vaccines resulting in protection against tumors even in the setting of pre-existing disease. We have identified some of the molecular mechanisms underlying the efficiency of the CRCL vaccine. We are now, in collaboration with Immunovative Ltd, initiating clinical trials evaluating the the safety and efficacy of the CRCL vaccine in humans. We are also working on improving the efficiency of CRCL by associating this vaccine with other immunotherapeutic approaches.
- Anti-tumoral role of Th-17 lymphocytes.
Th-17 lymphocytes represent a third effector CD4+ T cell lineage. They may play an important role in various autoimmune disorders and in the control of infections in humans. We are investigating the contribution of these lymphocytes in anticancer immunity and are developing approaches to harness their inflammatory potential against tumors.
- Role of tumor-killer dendritic cells(KDC) in cancer.
Beside their role as major antigen presenting cells, DC, when appropriately activated, may display a direct tumor killing activity. Conducted in collaboration with the National Institute of Health and Medical Research Unit 866 (University of Burgundy, France), this project aims at investigating the non-conventional cytotoxic function of dendritic cells, evaluating their potential therapeutic role and the reciprocal interaction between KDC and tumor-induced regulatory T cells.
Lab website: http://www.u.arizona.edu/~nrlarmon/TIL.htm
Publications:
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J. Fraszczak, M. Trad, D. Lakomy, D. Cathelin, N. Janikashvili, N. Sassi, V. Granci, A. Morizot, S. Audia, L. Lagrost, E. Katsanis, E. Solary, B. Bonnotte* and N. Larmonier*. Peroxynitrite-dependent killing of cancer cells and presentation of released tumor antigens by activated dendritic cells (In revision, The Journal of Immunology)
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N. Larmonier, N. Janikashvili, C. J. LaCasse, C. Larmonier, J. Cantrell, E. Situ, G. Li, B. Bonnotte and E. Katsanis. Imatinib mesylate suppresses CD4+CD25+ regulatory T cells and efficiently combines with immunotherapy to treat BCR-ABLnegative tumors. The Journal of Immunology. 181: 6955-6963. 2008
N. Larmonier, J. Cantrell, C. LaCasse, G. Li, N. Janikashvili, E. Situ, M. Sepassi, S. Andreansky and E. Katsanis. Chaperone-rich tumor cell lysate –mediated activation of antigen presenting cell resists regulatory T cell suppression. Journal of Leukocyte Biology, 83:1049-1059. 2008
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A. Nicolas*, D. Cathelin*, N. Larmonier, J. Fraszczak, P.E. Puig, A. Bouchot, A. Bateman, E. Solary, and B. Bonnotte. Dendritic cells trigger tumor cell death by a nitric oxide -dependent mechanism. The Journal of Immunology, 179: 812-818. 2007.
N. Larmonier, M. Marron, Y. Zeng, J. Cantrell, A. Romanoski, M. Sepassi, S. Thompson, X. Chen, S. Andreansky, and E. Katsanis. Tumor-derived CD4+CD25+ regulatory T cells suppression of dendritic cell function involves TGF-b and IL-10. Cancer Immunology and Immunotherapy. 56: 48-59. 2007.
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N. Larmonier, F. Ghiringhelli, E. Schmitt, A. Parcellier, D. Cathelin, C. Garrido, B. Chauffert, E. Solary, B. Bonnotte, and F. Martin. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide that allows immunotherapy of established tumors to be curative. European Journal of Immunology. 34: 336-344. 2004
Peer-reviewed publications
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