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Leukemia. 2018 Feb;32(2):429-437. doi: 10.1038/leu.2017.214. Epub 2017 Jul 5.

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy.

Author information

1
Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
2
Center for Cancer Immune Therapy, Department of Hematology, Copenhagen University Hospital at Herlev, Herlev, Denmark.
3
Department of Oncology, Copenhagen University Hospital at Herlev, Herlev, Denmark.
4
Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
5
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

Abstract

The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T cells were able to recognize several epitopes in the CALRmut C terminus. Next, we established a CALRmut-specific CD4+ T-cell clone by limiting dilution. These CD4+ T cells recognized autologous CALRmut monocytes and hematopoietic stem cells, and T-cell recognition of target cells was dependent on the presence of CALR. Furthermore, we showed that the CALRmut response was human leukocyte antigen (HLA)-DR restricted. Finally, we demonstrated that the CALRmut-specific CD4+ T cells, despite their phenotype, were cytotoxic to autologous CALRmut cells, and that the cytotoxicity was mediated by degranulation of the T cells. In conclusion, the CALR exon 9 mutations are targets for specific T cells and thus are promising targets for cancer immune therapy such as peptide vaccination in patients harboring CALR exon 9 mutations.

PMID:
28676668
DOI:
10.1038/leu.2017.214
[Indexed for MEDLINE]

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