High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals

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 CALR wt MPN-patients and in healthy individuals. Specific immune responses against epitopes in the mutant CALR peptide sequence were detected in both CALR wt 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.