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

Abstract

SUMMARY 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.

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…XBP1s also promotes tumorigenesis by assembling a transcription complex with HIF1α to transactivate target genes ) and up-regulating Snail expression to induce epithelial-to-mesenchymal transition (EMT) . XBP1s in tumor-associated dendritic cells promotes ovarian cancer by inhibiting anti-tumor immunity through abnormal lipid accumulation in tumor-associated dendritic cells (Cubillos-Ruiz et al 2015). In contrast, Xbp1-deficient IECs exhibit increased turnover through NFκB-dependent activation of STAT3, promoting colitisassociated cancer and spontaneous adenomatous polyposis coli (APC)-related tumors in mice , suggesting that XBP1 might act as a tumor suppressor in the intestine.…”

Targeting abnormal ER stress responses in tumors: A new approach to cancer immunotherapy

“…We established that DCs residing in human and mouse ovarian cancers exhibited robust IRE1a-XBP1 activation and overexpression of XBP1-dependent genes involved in the ER stress response. 9 In the tumor microenvironment, DCs demonstrated high levels of reactive oxygen species that promoted the generation of 4-hydroxynonenal (4-HNE), a lipid peroxidation byproduct that induced ER stress by directly modifying critical ER-resident proteins and chaperones. 9 Notably, 4-HNE has been shown to promote vascular inflammation and atherogenesis by triggering ER stress in endothelial cells.…”

“…9 In the tumor microenvironment, DCs demonstrated high levels of reactive oxygen species that promoted the generation of 4-hydroxynonenal (4-HNE), a lipid peroxidation byproduct that induced ER stress by directly modifying critical ER-resident proteins and chaperones. 9 Notably, 4-HNE has been shown to promote vascular inflammation and atherogenesis by triggering ER stress in endothelial cells. 10 Using conditional knockout mice, we found that sustained XBP1 activation by tDCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in three preclinical models of disease analyzed.…”

“…10 Using conditional knockout mice, we found that sustained XBP1 activation by tDCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in three preclinical models of disease analyzed. 9 Genome-wide transcriptional analyses revealed that constitutively active XBP1 induced a comprehensive triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support antitumor T cells. 9 Notably, it has been previously demonstrated that a major mechanism mediating DC dysfunction in cancer is in fact aberrant intracellular lipid accumulation, a process that interferes with normal DC antigen cross-presentation pathways.…”

“…9 Genome-wide transcriptional analyses revealed that constitutively active XBP1 induced a comprehensive triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support antitumor T cells. 9 Notably, it has been previously demonstrated that a major mechanism mediating DC dysfunction in cancer is in fact aberrant intracellular lipid accumulation, a process that interferes with normal DC antigen cross-presentation pathways. 11 Supporting this crucial concept, we found that DC-specific deletion of XBP1 extended host survival by converting tolerogenic tDCs into potent activators of type 1 immunity in ovarian cancer-infiltrating T cells.…”