Evasion of immunorecognition by breast cancer cells under diverse oxidative stress conditions is facilitated by the function of Protein Disulphide Isomerases (PDIs)

Immunosurveillance is the mechanism by which neoplastic tissues are identified and eliminated by the body’s immune system thereby preventing the development of many malignancies. Efficient presentation of tumor antigens to the cells of the immune system is an essential process determining the recognition and effective elimination of tumor cells by the immune system. Delineating the components of the antigen processing and presentation pathways and the molecular mechanisms governing the regulation of their function can facilitate the understanding of the evasion of immunosurveillance by cancer cells. Generation of increased levels of Reactive Oxygen Species (ROS) and endoplasmic reticulum stress are common characteristics of the hypoxic microenvironment of all solid tumors. The redox responsive chaperones of the endoplasmic reticulum including the oxidoreductase Protein Disulphide Isomerase (PDI) family member P4HB are key components of the antigen presentation machinery contributing to the selection and loading of the optimal antigen to MHC class I molecules. In this study the regulation of the P4HB function under diverse oxidative stress conditions and the subsequent retention or release of the MHC class I molecules from the ER were investigated. Our results indicate that estrogenic like hormones modify the cellular redox state of breast cancer cells leading to alterations of the P4HB oxidoreductase activity and subsequent differential expression of the classical versus non-classical MHC class I and its translocation to the cell surface thereby enabling cancer cells to escape immunosurveillance. Detailed understanding of the role of the P4HB in the regulation of immunorecognition can facilitate the development of individualized cancer immunotherapies.