Abstract
Mutations in exon 9 of the calreticulin gene (CALR) frequently occur in patients with chronic myeloproliferative neoplasms (MPN). Patients exhibit spontaneous cellular immune responses to epitopes derived from the mutant CALR C-terminus, and CALR-mutant-specific T cells recognize autologous CALR-mutant malignant cells. This study investigated whether CALR-mutant-specific T cells occur naturally in CALRwt MPN-patients and in healthy individuals. Specific immune responses against epitopes in the mutant CALR peptide sequence were detected in both CALRwt MPN-patients and in healthy individuals. Healthy donors displayed more frequent and stronger CALR-mutant specific T-cell responses compared to the responses identified in CALR-mutant MPN-patients. Several T-cell responses were identified in healthy donors directly ex vivo. Importantly, by running functional analyses on live-sorted immune cells from healthy donors, we showed that circulating CALR-mutant-specific immune cells are T-memory cells. These findings suggest, that healthy individuals acquire a CALR exon 9 mutation, but the immune system reacts and clears the mutant cells, and during this reaction generates CALR-mutant specific T-memory cells. We believe that these findings provide the evidence for tumor immune surveillance in MPN.
Highlights
In 2013, two independent research groups reported on the occurrence of somatic mutations in exon 9 of the calreticulin (CALR) gene in 75% of patients with Janus kinase 2 (JAK2)wt chronic myeloproliferative neoplasms (MPN)[1,2]
As the use of Fluorescence-activated cell sorting (FACS) for sorting TEM cells can potentially interfere with cell functionality, we looked further into the CALR-mutant-specific T-cell responses by sorting peripheral blood mononuclear cells (PBMC) from three healthy individuals using Magnetically activated cell sorting (MACS) to enrich for CD4+ T-memory cells (Tmem) and Tnaive
We previously described in detail that the immune system of CALR-mutant patients reacts to the mutant CALR C-terminus[3]
Summary
In 2013, two independent research groups reported on the occurrence of somatic mutations in exon 9 of the calreticulin (CALR) gene in 75% of patients with Janus kinase 2 (JAK2)wt chronic myeloproliferative neoplasms (MPN)[1,2]. We recently provided evidence that patients with CALR-mutant MPN exhibit frequent, spontaneous cellular immune responses against epitopes derived from the mutant CALR C-terminus[3], and that CALR-mutantspecific T-cells derived from patients can recognize and kill autologous CALR-mutant cells in a CALR-mutant dependent manner[4]. As such the CALR mutations generate an immunogenic antigen that could be used as target for cancer immune therapy[5]. In regard to immune responses to the BCR-ABL fusion transcript, one study showed responses in peripheral blood mononuclear cells (PBMC) from 3/18 healthy donors after stimulation in vitro with autologous dendritic cells that had been pulsed with a BCR-ABL peptide[8], whereas another study
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