The activity of our laboratory is focused on the understanding of the mechanisms that control the activation and regulation of T cell responses and on the development of new strategies of vaccination against tumors and infections.

Development of therapeutic anti-cancer vaccines. Based on the capacity of the adenylate cyclase (CyaA) to bind to dendritic cells (DC), we have developed a highly efficient vector capable of targeting a wide range of antigens to antigen presenting cells, leading to strong immune responses. We used this new vector to develop therapeutic vaccine candidates against cervical cancer and melanoma. Administration of CyaA vaccine with CpG and low-dose of cyclophosphamide completely overcame tumor-associated immunosuppression and eradicated large, established tumors in mice. Another anti-cancer therapeutic vaccine under development, the MAG-Tn3, was shown to capable of targeting dermal DC to induce immunity specific for the Tn carbohydrate tumor antigen. Several clinical trials are being organized to test these therapeutic vaccine candidates.

Analysis of immunosuppresion within tumor environment. Tumor immunosuppression represents the major cause of the failure of many cancer therapies. To understand and overcome these suppressive responses, we are analyzing the interaction between tumor cells and the immune system during tumor growth. We have identified several subsets of myeloid suppressor cells within the tumor tissue, showing different developing program. We are currently studying their interaction with regulatory T cells.

Analysis of T cell responses induced by dendritic cell subpopulations. Plasmacytoid DC (pDC) are characterized by their high capacity to produce type I IFNs after stimulation. We demonstrated that pDC are able to present both endogenous and exogenous antigens after activation leading to the induction of CD8⁺ T cell responses. These results suggest that pDC can play a role in both innate and adaptive immunity. The mechanisms of induction of presentation of exogenous antigens to CD8⁺ T cells (cross-presentation) by pDC are under investigation. Furthermore, we developed a mouse model lacking pDC to characterize their functions in vivo. We are using this model to decipher the role of pDC in the activation of natural killer cells and their involvement in tumor immunity.

Immune regulation and vaccine science in neonates. Understanding the innate and adaptive regulatory mechanisms responsible for the high susceptibility to infections in newborns will help to improve vaccine design. We found a crosstalk between neonatal Bregs cells and DC, following TLR activation, leading to impaired pro-inflammatory and Th1 responses. We also identified a regulatory role of neutrophils in the context of bacterial infection following co-activation of TLR and C-type lectin/Syk pathways. We are currently investigating, both in mice and humans, innate activation pathways that activate neonatal DC and bypass regulatory mechanisms to allow efficient priming of protective Th1/Th17 responses.

Anti-mycobacterial immunity. The live attenuated vaccine Mycobacterium bovis BCG (Bacillus Calmette-Guérin) is not able to protect efficiently against M. tuberculosis infection in the adult pulmonary tuberculosis. We developed an innovative strategy for the rational design of a new anti-mycobacterial vaccine by in vivo addressing of prominent mycobacterial antigens, i.e., proteins from ESX family, through a versatile approach, to diverse DC subsets through CD11c or CD11b beta-integrins or different C-type lectins and notably CD205. The potential of this vaccination strategy to control the pulmonary infection with virulent M. tuberculosis is currently in progress.

Keywords: Vaccines, neonate, CTL, dendritic cells, cancer, T cells, immunotherapy, anti-mycobacterial immunity

Zhang X, Deriaud E, Jiao X, Braun D, Leclerc C, Lo-Man R. (2007)Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells. J Exp Med., 204:1107-18.PMID: 17485512

Berraondo P, Nouzé C, Préville X, Ladant D, Leclerc C. (2007)Eradication of large tumors in mice by a tritherapy targeting the innate, adaptive, and regulatory components of the immune system. Cancer Res. 67:8847-55.PMID: 17875726

J. Mouries, G. Moron, G. Schlecht, N. Escriou, G. Dadaglio and C. Leclerc. (2008)Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation. Blood, 112: 3713-3722PMID: 18698004

X. Zhang, L. Majlessi, E. Deriaud, C. Leclerc and R. Lo-Man. (2009)Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity, 31:761-71.PMID: 19913447

Freire T, Zhang X, Dériaud E, Ganneau C, Vichier-Guerre S, Azria E, Launay O, Lo-Man R, Bay S, Leclerc C. (2010)Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant. Blood. 116:3526-36.PMID: 20720186