title: ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Pedro C
authors.initials: PC
authors.lastname: Silberman
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Sahil
authors.initials: S
authors.lastname: Chopra
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Song
authors.affiliation: Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bettigole
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Holcomb
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Lora H
authors.initials: LH
authors.lastname: Ellenson
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Caputo
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
authors.affiliation: 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.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003713:Dendritic Cells / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology*; D000071701:Regulatory Factor X Transcription Factors; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse