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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Calreticulin / genetics*
  • Cytotoxicity, Immunologic / drug effects
  • Exons / drug effects*
  • Exons / genetics
  • HLA Antigens / drug effects
  • HLA Antigens / genetics
  • HLA Antigens / immunology
  • Humans
  • Male
  • Mutation / drug effects*
  • Mutation / genetics
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Phenotype
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / immunology
  • Thrombocythemia, Essential / genetics
  • Thrombocythemia, Essential / immunology
  • Vaccines, Subunit / immunology
  • Vaccines, Subunit / therapeutic use*

Substances

  • Calreticulin
  • HLA Antigens
  • Vaccines, Subunit
  • calreticulin, human