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

Publication ,  Journal Article
Cubillos-Ruiz, JR; Silberman, PC; Rutkowski, MR; Chopra, S; Perales-Puchalt, A; Song, M; Zhang, S; Bettigole, SE; Gupta, D; Holcomb, K ...
Published in: Cell
June 18, 2015

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.

Duke Scholars

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 18, 2015

Volume

161

Issue

7

Start / End Page

1527 / 1538

Location

United States

Related Subject Headings

  • X-Box Binding Protein 1
  • Transcription Factors
  • T-Lymphocytes
  • Regulatory Factor X Transcription Factors
  • Ovarian Neoplasms
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Lipid Peroxidation
  • Humans
 

Citation

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Cubillos-Ruiz, J. R., Silberman, P. C., Rutkowski, M. R., Chopra, S., Perales-Puchalt, A., Song, M., … Glimcher, L. H. (2015). ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell, 161(7), 1527–1538. https://doi.org/10.1016/j.cell.2015.05.025
Cubillos-Ruiz, Juan R., Pedro C. Silberman, Melanie R. Rutkowski, Sahil Chopra, Alfredo Perales-Puchalt, Minkyung Song, Sheng Zhang, et al. “ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.Cell 161, no. 7 (June 18, 2015): 1527–38. https://doi.org/10.1016/j.cell.2015.05.025.
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 Jun 18;161(7):1527–38.
Cubillos-Ruiz, Juan R., et al. “ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.Cell, vol. 161, no. 7, June 2015, pp. 1527–38. Pubmed, doi:10.1016/j.cell.2015.05.025.
Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole SE, Gupta D, Holcomb K, Ellenson LH, Caputo T, Lee A-H, Conejo-Garcia JR, Glimcher LH. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell. 2015 Jun 18;161(7):1527–1538.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 18, 2015

Volume

161

Issue

7

Start / End Page

1527 / 1538

Location

United States

Related Subject Headings

  • X-Box Binding Protein 1
  • Transcription Factors
  • T-Lymphocytes
  • Regulatory Factor X Transcription Factors
  • Ovarian Neoplasms
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Lipid Peroxidation
  • Humans