Immunobiology of Dendritic Cells and Immunotherapy

Research project

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 and as infectious agents in order to kill tumor cells both because they are neoplastic and because they are infected

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.

The first one studies a possible use of an attenuated strain of Salmonella to initiate immune responses against tumor cells. We have described that intratumoral injection of Salmonella induces two effects: first, it facilitates the recruitment of immune cells within the tumor site and renders the tumor visible to the immune system; second, it generates an immunostimulatory environment that leads to the presentation of tumor antigens. This results in the induction of a specific anti-tumor response that can act also on lesions that are distant from the treated ones. We are currently understanding how Salmonella facilitates the cross-presentation of tumor antigens. We also identified a strain of Salmonella that is capable of eliciting a systemic anti-salmonella response but not a local response. This allows the repeated administrations of the vaccine without the side effects of a local neutralizing anti-salmonella response that would impede its entrance in our body during subsequent administrations.

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 (Fig. 1). A question that intrigued our laboratory was to understand how dendritic cells could discriminate between the encountered luminal bacteria. We found that epithelial cells strongly control the function of dendritic cells and participate in maintaing the intestinal immune homeostasis. This allows the dendritic cells to tolerate intestinal bacteria while initiating an immune response towards pathogens. We are now dissecting out the molecular mechanisms of epithelial cell-dendritic cell interactions.