Our ability to defend ourselves against infectious diseases greatly depends on our capacity to mount an effective immune response. This is achieved through two complementary aspects, the innate and adaptive responses. The proverbial bridge that interconnects both aspects is the T cell which acts like a maestro able to direct the activation of a variety of effector cells by way of secreted proteins, the cytokines and by cell-cell contacts. Proper activation of the T cell depends on the high affinity interaction of its major cell surface receptor, the T cell receptor (TCR), with the major surface receptor of antigen presenting cells (APC), known as the Major Histocompatibility Complex (MHC), as it presents a foreign peptide antigen (pMHC).
Due to the nature of cancer, the antigen repertoire generated by APCs in a tumor context is very similar to that of the host and the peptides presented in these environments rarely confer high affinity recognition by the TCR resulting in inefficient T cell activation. Also, the micro- environment of the tumor is highly enriched in cytokines that muffle the T cell activation and promotes irresponsiveness. Irresponsive T cells are crucial for the immunological escape of the tumor as they, themselves, further block the activation of newly arriving T cells and other effector cells. The major components identified as being responsible for the establishment of immune tolerance are derived cytokines and reactive oxygen species.
Though we know the downstream effects of the tumor environment on the immune response, the molecular pathways affected are still poorly understood. The goal of our research program is to characterize the molecular effects of the tumor microenvironment on the formation of the immunological synapse of T cells from tumors. We will be using cutting edge microscopy assays as well as gene replacement therapies to determine what is being affected and how to modify the T cell to reverse these effects. Our projects are also intended to determine the role of zinc transporters in the control and improvement of the activation threshold of TCR for low affinity pMHC. The role of these carriers will be studied in different mouse models.