Abstract
The IRE1α/XBP1s signaling pathway is an arm of the unfolded protein response (UPR) that safeguards the fidelity of the cellular proteome during endoplasmic reticulum (ER) stress, and that has also emerged as a key regulator of dendritic cell (DC) homeostasis. However, in the context of DC activation, the regulation of the IRE1α/XBP1s axis is not fully understood. In this work, we report that cell lysates generated from melanoma cell lines markedly induce XBP1s and certain members of the UPR such as the chaperone BiP in bone marrow derived DCs (BMDCs). Activation of IRE1α endonuclease upon innate recognition of melanoma cell lysates was required for amplification of proinflammatory cytokine production and was necessary for efficient cross-presentation of melanoma-associated antigens without modulating the MHC-II antigen presentation machinery. Altogether, this work provides evidence indicating that ex-vivo activation of the IRE1α/XBP1 pathway in BMDCs enhances CD8+ T cell specific responses against tumor antigens.
Highlights
Dendritic cells (DCs) are an heterogeneous family of leukocytes competent to instruct antigen-specific immune responses [1]
It has been shown that myeloid cells activate the IRE1α/XBP1 spliced (XBP1s) axis in response to microbial ligands of Toll-Like Receptors (TLR), RIG-I-like receptors and with molecules expressed by tumors [25,26,27,28,29, 32, 33]
We generated in vitro cultures of bone marrow (BM) cells cultured in presence of the cytokine FMS-like tyrosinase kinase 3 ligand (FLT3L), which is a culture that generates an heterogeneous mix of cell equivalents of conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), and plasmacytoid DC (pDC) (Supplemental Figure 1B) [10]
Summary
Dendritic cells (DCs) are an heterogeneous family of leukocytes competent to instruct antigen-specific immune responses [1]. CDC1s are highly efficient at priming CD8+ T cell responses in vivo to cell-associated antigens through a process termed “cross-presentation” [7]. IRE1α Favors Cross-Presentation of Melanoma Antigens express the surface markers CD11b and CD172a (SIRPα), the transcription factors Irf, Klf, and Notch are recognized for modulating CD4+ T cell responses [2, 4, 5]. Cell equivalents of cDCs/pDCs and monocyte-derived DCs can be generated upon ex-vivo treatment with FMS-like tyrosinase kinase 3 ligand (FLT3L) or granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively [9, 10]. The process of antigen cross-presentation, which is essential for eliciting cytotoxic T cell immunity against tumors, can be efficiently executed by cDC1s, and by GM-CSF derived DCs through different transcriptional programs [11]
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