title: Molecular Pathways: Immunosuppressive Roles of IRE1α-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment.
abstract: 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 IRE1α-XBP1 arm of 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 IRE1α-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 tumor-associated DCs, the biologic processes altered by aberrant IRE1α-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.
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, New York. Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York. jur2016@med.cornell.edu lglimche@med.cornell.edu.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bettigole
authors.affiliation: Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. jur2016@med.cornell.edu lglimche@med.cornell.edu.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism* / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology*; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*
chemical_list: D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases