Molecular Pathways: Immunosuppressive Roles of IRE1a-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment

The endoplasmic reticulum (ER) is a massive cytoplasmic membrane network that functions primarily to ensure proper folding and posttranslational modification of newly synthesized secreted and transmembrane proteins. Abnormal accumulation of unfolded proteins in this organelle causes a state of "ER stress," which is a hallmark feature of various diseases, including cancer, neurodegeneration, and metabolic dysfunction. Cancer cells exploit the IRE1a-XBP1 armof the ER stress response to efficiently adjust their protein-folding capacity and ensure survival under hostile tumor microenvironmental conditions. However, we recently found that dendritic cells (DC) residing in the ovarian cancer microenvironment also experience sustained ER stress and demonstrate persistent activation of the IRE1a-XBP1 pathway. This previously unrecognized process disrupts metabolic homeostasis and antigen-presenting capacity in DCs, thereby crippling their natural ability to support the protective functions of infiltrating antitumor T cells. In this review, we briefly discuss some of the mechanisms that fuel ER stress in tumorassociated DCs, the biologic processes altered by aberrant IRE1a-XBP1 signaling in these innate immune cells, and the unique immunotherapeutic potential of targeting this pathway in cancer hosts. Clin Cancer Res; 22(9); 2121–6. 2016 AACR.