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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • June 18, 2015

Published In

Volume / Issue

  • 161 / 7

Start / End Page

  • 1527 - 1538

PubMed ID

  • 26073941

Pubmed Central ID

  • PMC4580135

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2015.05.025


  • eng

Conference Location

  • United States