ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis
By J. Cubillos-Ruiz, Pedro C Silberman, Melanie R Rutkowski, Sahila Chopra, A. Perales-Puchalt, Minkyung Song, S. Zhang, Sarah Bettigole, D. Gupta, K. Holcomb and 5 more. Cell, 2015
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SUMMARY Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum (ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.
Subfields: Cell Biology, Epidemiology, Immunology
View Paper: https://www.semanticscholar.org/paper/2a60154e4d8e0c2413bbf1837dbe492c53e343c4
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Citations in the corpus
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “…Damaging molecules, including ROS and lipid peroxidation byproduct 4-HNE, the marker of ferroptosis, accumulate in ovarian cancer-associated DCs. 348,349 This accumulation promotes endoplasmic reticulum stress response and X-box binding protein 1 (XBP1) activation, ultimately impairing the…”
- Metabolic Instruction of Immunity (2017, neutral): “Like macrophages in atherosclerotic plaques, DCs in the tumor can accumulate oxidized lipoproteins through scavenger receptor mediated internalization and formation of lipid droplets, which can ultimately impair their ability to cross-present tumor antigens and activate T cells (Cubillos-Ruiz et al.”
- Cholesterol induces CD8+ T-cell exhaustion in the tumor microenvironment (2019, neutral): “, 2014) and a transcription factor that regulates expression of various target gene sets (Cubillos-Ruiz et al., 2015), was highly upregulated in cholesterol-treated CD8+ T cells (Figure 4C and 4D).”
- Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. (2019, background): “illustrated how endoplasmic reticulum stress in tumor-associated dendritic cells promotes tumor growth and dampens anti-cancer immunity [223].”
- Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, neutral): “ROS can also generate highly reactive peroxidized lipid byproducts, which form destructive covalent adducts with various ER chaperones (Cubillos-Ruiz et al., 2015; Vladykovskaya et al., 2012).”