TY - JOUR
T1 - The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy
AU - Holmström, Morten Orebro
AU - Martinenaite, E.
AU - Ahmad, S. M.
AU - Met, Ö.
AU - Friese, C.
AU - Kjær, Lasse
AU - Riley, C. H.
AU - Thor Straten, P.
AU - Svane, I. M.
AU - Hasselbalch, Hans Karl
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.
UR - http://www.scopus.com/inward/record.url?scp=85033351671&partnerID=8YFLogxK
U2 - 10.1038/leu.2017.214
DO - 10.1038/leu.2017.214
M3 - Article
C2 - 28676668
AN - SCOPUS:85033351671
SN - 0887-6924
VL - 32
SP - 429
EP - 437
JO - Leukemia
JF - Leukemia
IS - 2
ER -