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 af dette arbejde

Institut for Klinisk Medicin

14 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	8
Tidsskrift	Blood Cancer Journal
Vol/bind	9
Udgave nummer	2
ISSN	2044-5385
DOI	https://doi.org/10.1038/s41408-018-0166-4
Status	Udgivet - 2019

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10.1038/s41408-018-0166-4Licens: CC BY

High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individualsForlagets udgivne version, 2,9 MBLicens: CC BY

Citationsformater

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, bind 9, nr. 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",

language = "English",

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journal = "Blood Cancer Journal",

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TY - JOUR

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

Abstract

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