PMID- 26073941 OWN - NLM STAT- MEDLINE DCOM- 20150831 LR - 20220421 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 161 IP - 7 DP - 2015 Jun 18 TI - ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. PG - 1527-38 LID - S0092-8674(15)00575-9 [pii] LID - 10.1016/j.cell.2015.05.025 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Cubillos-Ruiz, Juan R AU - Cubillos-Ruiz JR AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Silberman, Pedro C AU - Silberman PC AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Rutkowski, Melanie R AU - Rutkowski MR AD - Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. FAU - Chopra, Sahil AU - Chopra S AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Perales-Puchalt, Alfredo AU - Perales-Puchalt A AD - Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. FAU - Song, Minkyung AU - Song M AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Zhang, Sheng AU - Zhang S AD - Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA. FAU - Bettigole, Sarah E AU - Bettigole SE AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA; Harvard Graduate Program in Immunology, Harvard University, Boston, MA 02115, USA. FAU - Gupta, Divya AU - Gupta D AD - Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Holcomb, Kevin AU - Holcomb K AD - Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Ellenson, Lora H AU - Ellenson LH AD - Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Caputo, Thomas AU - Caputo T AD - Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Lee, Ann-Hwee AU - Lee AH AD - Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Conejo-Garcia, Jose R AU - Conejo-Garcia JR AD - Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. FAU - Glimcher, Laurie H AU - Glimcher LH AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lglimche@med.cornell.edu. LA - eng SI - GEO/GSE68472 GR - R01CA157664/CA/NCI NIH HHS/United States GR - R01CA112663/CA/NCI NIH HHS/United States GR - R01 CA112663/CA/NCI NIH HHS/United States GR - P30 CA010815/CA/NCI NIH HHS/United States GR - R01CA124515/CA/NCI NIH HHS/United States GR - S10 RR025449/RR/NCRR NIH HHS/United States GR - R01 CA124515/CA/NCI NIH HHS/United States GR - R01 CA157664/CA/NCI NIH HHS/United States GR - R01 DK082448/DK/NIDDK NIH HHS/United States GR - 1S10RR025449-01/RR/NCRR NIH HHS/United States GR - R01 CA178687/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150611 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (DNA-Binding Proteins) RN - 0 (Regulatory Factor X Transcription Factors) RN - 0 (Transcription Factors) RN - 0 (X-Box Binding Protein 1) RN - 0 (XBP1 protein, human) RN - 0 (Xbp1 protein, mouse) SB - IM CIN - Cell. 2015 Jun 18;161(7):1492-3. PMID: 26091029 CIN - Nat Rev Immunol. 2015 Aug;15(8):465. PMID: 26139351 CIN - Nature. 2015 Jul 16;523(7560):294-5. PMID: 26178959 CIN - Cell Res. 2015 Sep;25(9):989-90. PMID: 26227962 MH - Animals MH - DNA-Binding Proteins/*metabolism MH - Dendritic Cells/*pathology MH - *Endoplasmic Reticulum Stress MH - Female MH - Humans MH - Lipid Peroxidation MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Ovarian Neoplasms/*immunology/*pathology MH - Regulatory Factor X Transcription Factors MH - T-Lymphocytes/immunology MH - Transcription Factors/*metabolism MH - X-Box Binding Protein 1 PMC - PMC4580135 MID - NIHMS691029 EDAT- 2015/06/16 06:00 MHDA- 2015/09/01 06:00 PMCR- 2016/06/18 CRDT- 2015/06/16 06:00 PHST- 2014/08/25 00:00 [received] PHST- 2015/02/03 00:00 [revised] PHST- 2015/04/28 00:00 [accepted] PHST- 2015/06/16 06:00 [entrez] PHST- 2015/06/16 06:00 [pubmed] PHST- 2015/09/01 06:00 [medline] PHST- 2016/06/18 00:00 [pmc-release] AID - S0092-8674(15)00575-9 [pii] AID - 10.1016/j.cell.2015.05.025 [doi] PST - ppublish SO - Cell. 2015 Jun 18;161(7):1527-38. doi: 10.1016/j.cell.2015.05.025. Epub 2015 Jun 11.