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Mol Cell. 2019 Nov 23. pii: S1097-2765(19)30833-0. doi: 10.1016/j.molcel.2019.11.004. [Epub ahead of print]

Immunosuppression by Mutated Calreticulin Released from Malignant Cells.

Author information

1
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France.
2
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France; Université Paris-Saclay, Villejuif, France.
3
Université Paris-Saclay, Villejuif, France; INSERM, UMR 1170, Villejuif, France; Gustave Roussy Comprehensive Cancer Center, Villejuif, France.
4
Gustave Roussy Comprehensive Cancer Center, Villejuif, France; INSERM, U1015, Villejuif, France; Center of Clinical Investigations, CIC1428, Villejuif, France.
5
Université of Paris, Paris, France; INSERM, U1151, Paris, France; CNRS UMR8253, Paris, France.
6
Cell Biology and Cancer Unit, Institut Curie, PSL Research University, CNRS, Paris, France.
7
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad de Oviedo, 33006 Oviedo, Spain.
8
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad de Oviedo, 33006 Oviedo, Spain.
9
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France. Electronic address: captain.olsen@gmail.com.
10
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM UMR 1138, Paris, France; Sorbonne Université, Paris, France; Université of Paris, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China; Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Electronic address: kroemer@orange.fr.

Abstract

Mutations affecting exon 9 of the CALR gene lead to the generation of a C-terminally modified calreticulin (CALR) protein that lacks the KDEL endoplasmic reticulum (ER) retention signal and consequently mislocalizes outside of the ER where it activates the thrombopoietin receptor in a cell-autonomous fashion, thus driving myeloproliferative diseases. Here, we used the retention using selective hooks (RUSH) assay to monitor the trafficking of CALR. We found that exon-9-mutated CALR was released from cells in response to the biotin-mediated detachment from its ER-localized hook, in vitro and in vivo. Cellular CALR release was confirmed in suitable mouse models bearing exon-9-mutated hematopoietic systems or tumors. Extracellular CALR mediated immunomodulatory effects and inhibited the phagocytosis of dying cancer cells by dendritic cells (DC), thereby suppressing antineoplastic immune responses elicited by chemotherapeutic agents or by PD-1 blockade. Altogether, our results demonstrate paracrine immunosuppressive effects for exon-9-mutated CALR.

KEYWORDS:

CD47 blockade; ICD; PD-1; RUSH; calreticulin; immunogenic cell death; immunosuppression; phagocytosis; retention using selective hooks

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