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Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells
Published on: January 5, 2018
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Immunosuppression by Mutated Calreticulin Released from Malignant Cells.
Peng Liu1, Liwei Zhao2, Friedemann Loos1
1Metabolomics 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.
Molecular Cell
|December 2, 2019
Summary
Mutations in the CALR gene cause a protein to be released from cells, suppressing immune responses against cancer. This extracellular CALR protein interferes with the immune system
Area of Science:
- Molecular Biology
- Immunology
- Cancer Biology
Background:
- Mutations in exon 9 of the calreticulin (CALR) gene produce a C-terminally altered CALR protein.
- This altered protein lacks the KDEL endoplasmic reticulum (ER) retention signal, leading to its mislocalization outside the ER.
- Outside the ER, the mutated CALR protein activates the thrombopoietin receptor, driving myeloproliferative diseases.
Purpose of the Study:
- To investigate the trafficking and release of exon-9-mutated CALR.
- To determine the extracellular functions of mutated CALR.
- To elucidate the role of mutated CALR in immune suppression within the tumor microenvironment.
Main Methods:
- Utilized the retention using selective hooks (RUSH) assay to track CALR trafficking.
- Monitored CALR release in vitro and in vivo using biotin-mediated detachment.
- Confirmed cellular CALR release in mouse models with mutated CALR-bearing hematopoietic systems or tumors.
Main Results:
- Exon-9-mutated CALR was released from cells upon biotin-mediated detachment.
- Cellular release of mutated CALR was confirmed in relevant mouse models.
- Extracellular mutated CALR exhibited immunomodulatory effects, inhibiting phagocytosis of cancer cells by dendritic cells (DCs).
- This inhibition suppressed anti-cancer immune responses induced by chemotherapy or PD-1 blockade.
Conclusions:
- Exon-9-mutated CALR is released extracellularly.
- Extracellular mutated CALR mediates paracrine immunosuppressive effects.
- Mutated CALR impairs anti-tumor immunity by inhibiting dendritic cell phagocytosis, thus promoting tumor immune evasion.
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