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

Morten O. Holmström; Shamaila M. Ahmad; Uffe Klausen; Simone K. Bendtsen; Evelina Martinenaite; Caroline H. Riley; Inge M. Svane; Lasse Kjær; Vibe Skov; Christina Ellervik; Niels Pallisgaard; Hans C. Hasselbalch; Mads H. Andersen

doi:10.1038/s41408-018-0166-4

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

Morten O. Holmström^*, Shamaila M. Ahmad, Uffe Klausen, Simone K. Bendtsen, Evelina Martinenaite, Caroline H. Riley, Inge M. Svane, Lasse Kjær, Vibe Skov, Christina Ellervik, Niels Pallisgaard, Hans C. Hasselbalch, Mads H. Andersen

^*Corresponding author for this work

Department of Clinical Medicine

14 Citations (Scopus)

47 Downloads (Pure)

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.

Original language	English
Article number	8
Journal	Blood Cancer Journal
Volume	9
Issue number	2
ISSN	2044-5385
DOIs	https://doi.org/10.1038/s41408-018-0166-4
Publication status	Published - 2019

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High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individualsFinal published version, 2.9 MBLicence: CC BY

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Holmström, M. O., Ahmad, S. M., Klausen, U., Bendtsen, S. K., Martinenaite, E., Riley, C. H., Svane, I. M., Kjær, L., Skov, V., Ellervik, C., Pallisgaard, N., Hasselbalch, H. C., & Andersen, M. H. (2019). High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals. Blood Cancer Journal, 9(2), [8]. https://doi.org/10.1038/s41408-018-0166-4

Holmström, MO, Ahmad, SM, Klausen, U, Bendtsen, SK, Martinenaite, E, Riley, CH, Svane, IM, Kjær, L, Skov, V, Ellervik, C, Pallisgaard, N, Hasselbalch, HC & Andersen, MH 2019, 'High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals', Blood Cancer Journal, vol. 9, no. 2, 8. https://doi.org/10.1038/s41408-018-0166-4

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

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.",

author = "Holmstr{\"o}m, {Morten O.} and Ahmad, {Shamaila M.} and Uffe Klausen and Bendtsen, {Simone K.} and Evelina Martinenaite and Riley, {Caroline H.} and Svane, {Inge M.} and Lasse Kj{\ae}r and Vibe Skov and Christina Ellervik and Niels Pallisgaard and Hasselbalch, {Hans C.} and Andersen, {Mads H.}",

year = "2019",

doi = "10.1038/s41408-018-0166-4",

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T1 - High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals

AU - Holmström, Morten O.

AU - Ahmad, Shamaila M.

AU - Klausen, Uffe

AU - Bendtsen, Simone K.

AU - Martinenaite, Evelina

AU - Riley, Caroline H.

AU - Svane, Inge M.

AU - Kjær, Lasse

AU - Skov, Vibe

AU - Ellervik, Christina

AU - Pallisgaard, Niels

AU - Hasselbalch, Hans C.

AU - Andersen, Mads H.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s41408-018-0166-4

DO - 10.1038/s41408-018-0166-4

M3 - Journal article

C2 - 30655510

AN - SCOPUS:85060157663

SN - 2044-5385

VL - 9

JO - Blood Cancer Journal

JF - Blood Cancer Journal

IS - 2

M1 - 8

ER -

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

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