Immunobiology of Dendritic Cells and Immunotherapy
Maria Rescigno, PhD
European Institute of Oncology, Dept. of Experimental Oncology
Via Ripamonti 435, I-20141 Milan, Italy
Dendritic cells (DC) comprise a family of professional antigen presenting cells unique in their capacity to modulate T cell responses. DC play a primary role in pathogen protection, in central and peripheral tolerance and in anticancer immune responses. Understanding basic mechanisms governing DC function in biology and pathology can be instrumental to unravel how an immune response is initiated and to shape new protocols for immune intervention. In our unit we study the interaction of DC with recombinant bacteria both in vitro and in vivo with the aim of establishing new protocols for cancer immunotherapy. We have proposed bacteria as tumor antigen delivery systems to load DC in vitro or directly in vivo because of their capacity to simultaneously deliver antigenic and activation stimuli to DC. Bacteria can be used as 'trojan' horses to deliver self antigens (as tumor antigens) in a non-self context thus fooling the immune system and inducing a strong response towards the tumor antigen, which could be otherwise tolerated.
Two lines of research are being developed in this unit.
Fig. 1, Dendritic cells extend protrusions in the gut lumen to directly interact with bacteria. Dendritic cells are in green, epithelial cells in red.
Two lines of research are being developed in this unit. The first one is aimed at identifying new approaches to target DC with recombinant bacteria both in vitro and in vivo; the second one is aimed at understanding basic mechanisms governing the interplay of DC with epithelial cells and different classes of bacteria at mucosal surfaces. For the first line of research we have shown that bacteria expressing tumor associated antigens can be safely used to target DC in vitro and in vivo. Different bacterial strains (including attenuated strains of Salmonella typhimurium) can be employed to preferentially initiate systemic versus mucosal immune responses. Tumor protection against melanoma in mice both in vaccination and therapeutic approaches could be detected. The second line of research is based on the observation that dendritic cells can engulf directly bacteria across mucosal epithelia by intercalating between epithelial cells and by establishing new tight-junctions like structures with neighboring epithelial cells. The role of pathogenic versus commensal bacteria in governing DC-epithelial cells interplay is currently being analyzed in terms of subsequent activation of immune system cells including T and B lymphocytes.