The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy
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The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. / Holmstrom, M. O.; Martinenaite, E.; Ahmad, S. M.; Met, O.; Friese, C.; Kjaer, L.; Riley, C. H.; Straten, P. thor; Svane, I. M.; Hasselbalch, H. C.; Andersen, M. H.
I: Leukemia, Bind 32, Nr. 2, 01.02.2018, s. 429-437.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy
AU - Holmstrom, M. O.
AU - Martinenaite, E.
AU - Ahmad, S. M.
AU - Met, O.
AU - Friese, C.
AU - Kjaer, L.
AU - Riley, C. H.
AU - Straten, P. thor
AU - Svane, I. M.
AU - Hasselbalch, H. C.
AU - Andersen, M. H.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
U2 - 10.1038/leu.2017.214
DO - 10.1038/leu.2017.214
M3 - Journal article
C2 - 28676668
VL - 32
SP - 429
EP - 437
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 2
ER -
ID: 190648096