| The detection and removal of cancer by the immune system is a complex, highly orchestrated process requiring sequences of cell-cell interactions between immune cells and other cells of the body. Of fundamental importance during these cell-to-cell communications is the presentation of small peptides via major histocompatibility (MHC) class I molecules. The seminal events initiating T cell anti-tumor responses arise out of the physical interaction of T cells with antigen presenting cells (APCs), which when activated by pathogenic states in the body, display peptide antigens on MHC molecules in combination with stimulatory signals. As a result, T cells that perceive presented antigen via their T cell receptor are activated and are able to respond with effector functions directed at cells presenting this specific peptide-MHC complex on their surface. Thus, activated T cells interact with both normal and cancerous cells and must distinguish differences based on the presentation of tumor antigens via MHC. Before their presentation on all nucleated cells, MHC class I molecules are assembled in the endoplasmic reticulum (ER) in a regulated process, completed with the assistance of several ER resident proteins. Clinical findings in pancreatic cancer patients suggest that shortcomings in the above processes, such as a lack of tumor infiltration by T cells or APCs, or tumor cell disruption of MHC class I antigen presentation, may promote tumor escape from the immune system and disease progression.; In this dissertation, utilizing a murine model of pancreatic cancer, I have shown that a novel immunotherapeutic facilitating T cell and APC trafficking to developing pancreatic tumors promotes local and systemic anti-tumor immune responses. In related work with this model, I also defined how alterations in MHC class I assembly and presentation affect pancreatic cancer in vitro and in vivo recognition by immune cells. In particular, I used this model of pancreatic cancer to probe the role of the ER chaperone, tapasin in tumor antigen presentation and immune recognition. Finally, I demonstrate a specific region of Tapasin, as well amino acids of the MHC class I heavy chain, which influence the assembly and antigen presentation function of the MHC class I molecule. |
