The ER Stress Factor XBP1 Inhibits Antitumor Immune Responses

Activation of endoplasmic reticulum (ER) stress responses, including the transcription factor X-box binding protein 1 (XBP1), has been shown to directly promote tumor growth, metastasis, and drug resistance in various cancers. Cubillos-Ruiz and colleagues hypothesized that the ER stress sensor XBP1 also drives ovarian cancer progression by inhibiting dendritic cells (DC), which induce T-cell–mediated protective antitumor responses and are often dysregulated in ovarian tumors. In support of this idea, enhanced activation of XBP1 in tumor-associated dendritic cells (tDC) was observed in mice bearing aggressive ovarian tumors and in human ovarian cancer samples. Specific depletion of Xbp1 in DCs inhibited primary and metastatic tumor growth and prolonged survival in multiple preclinical mouse models of ovarian cancer, demonstrating that expression of XBP1 in tDCs is necessary for disease progression. Constitutive activation of XBP1 in tDCs was mediated by reactive oxygen species–dependent generation of intracellular lipid peroxidation byproducts and induction of sustained ER stress, and resulted in increased expression of XBP1-controlled triglyceride biosynthetic genes in tDCs. Ovarian cancer–infiltrating DCs lacking XBP1 exhibited decreased intracellular lipid and triglyceride levels, which have been implicated in the regulation of DC-mediated antitumor immune responses. Indeed, reduced lipid accumulation in XBP1-deficient tDCs increased their antigen-presenting capacity, resulting in enhanced T-cell infiltration and activation at tumor sites. Similarly, nanoparticle-mediated XBP1 silencing in tDCs augmented T-cell–dependent antitumor immunity, decreased metastasis, and increased survival in tumor-bearing mice. These results identify XBP1 as a key regulator of DC lipid homeostasis and function and suggest the ER stress response as a potential therapeutic target to improve the immune response to cancer.

Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 2015;161:1527–38.

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