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Molecular Pathways: Immunosuppressive Roles of IRE1??XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment #MMPMID26979393
Cubillos-Ruiz JR; Bettigole SE; Glimcher LH
Clin Cancer Res 2016[May]; 22 (9): 2121-6 PMID26979393show ga
The endoplasmic reticulum (ER) is a massive cytoplasmic membrane network that functions primarily to ensure proper folding and post-translational modification of newly synthesized secretory 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 IRE1?-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 (DCs) residing in the ovarian cancer microenvironment also experience sustained ER stress and demonstrate persistent activation of the IRE1?-XBP1 pathway. This previously unrecognized process disrupts metabolic homeostasis and antigen-presenting capacity in DCs, thereby crippling their natural ability to support the protective function of infiltrating anti-tumor T cells. In this review, we briefly discuss some of the mechanisms that fuel ER stress in tumor-associated DCs, the biological processes altered by aberrant IRE1?-XBP1 signaling in these innate immune cells, and the unique immunotherapeutic potential of targeting this pathway in cancer hosts.