Format

Send to

Choose Destination
Cell. 2015 Jun 18;161(7):1527-38. doi: 10.1016/j.cell.2015.05.025. Epub 2015 Jun 11.

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.

Author information

1
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.
2
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
3
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
4
Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA.
5
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.
6
Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY 10065, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
8
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.

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.

PMID:
26073941
PMCID:
PMC4580135
DOI:
10.1016/j.cell.2015.05.025
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center