1. Identify the physical site and process by which tumor-reactive T cells are activated
We have recently sequenced the T cell clones that migrate into the tumor site following treatment with tumor-binding antibodies. Additionally, we have established an experimental model which enables us to identify which of these T cells reacts to tumor antigens and to subsequently clone the relevant T cell receptor. We are currently striving to generate a unique and novel mouse model for labeling T cells after they recognize tumor antigens. Taken together, the aim of this project is to provide a precise and detailed documentation of the anatomical site and the process through which tumor-reactive T cells are activated and recruited.
2. Determine the DC subsets which activate tumor-reactive T cells and the mechanism by which this activation is achieved.
We have recently identified a number of dendritic cell subsets thatbecome activated in mice treated with tumor-binding antibodies. Nonetheless, The exact DC subset required for antigen presentation, and the exact process this subset performs remains unclear. Therefore, in this project we are working to generate a number of transgenic and knock-in mouse models for labelling activated dendritic cells in a tissue-specific manner.Identification of the DC subsets most prominent in the induction of antibody-mediated tumor immunity will not only provide a novel prognostic marker, but may also comprise a novel anti-cancer immunotherapeutic approach centered upon increasing the prevalence of that subset.
3. Elucidate the biological basis for the interactions between T cell and antibodies
We have discovered that a single injection of tumor-reactive T cells, administered concomitantly with anti-tumor antibodies,induces complete rejection of large and established tumor lesions.However, as T cells do not express antibody receptors, the basis for these interactions and how they promote such remarkable anti-tumor responses remains incompletely understood. Therefore, the aim of this project is to address theunderlying mechanism by which T cells and antibodies interact; this will be achieved through mapping of the signaling cascade and molecular pathways in T cells. Resolving these issues willgreatly assist in the design of novel and more potent immunotherapies aimed at complete tumor clearance.