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Front Immunol. 2019 Jan 4;9:3050. doi: 10.3389/fimmu.2018.03050. eCollection 2018.

IRE1α Activation in Bone Marrow-Derived Dendritic Cells Modulates Innate Recognition of Melanoma Cells and Favors CD8+ T Cell Priming.

Author information

1
Program of Immunology, Laboratory of Immunology and Cellular Stress, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile.
2
Programa de Doctorado en Biotecnología, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.
3
Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, Santiago, Chile.
4
Program of Immunology, Laboratory of Antitumor Immunity, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
5
Laboratory of Immunoncology, Fundacion Ciencia & Vida, Santiago, Chile.
6
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
7
Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.
8
Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Santiago, Chile.
9
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.

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.

KEYWORDS:

IRE1α; UPR; XBP1s; cross-presentation; dendritic cell; melanoma

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