Therapeutic activity of GARP:TGF-β1 blockade in murine primary myelofibrosis
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-β1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-β1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-β1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-β1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-β1 activation by GARP-expressing cells. GARP:TGF-β1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-β1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-β1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:141 |
|---|---|
| Enthalten in: |
Blood - 141(2023), 5 vom: 02. Feb., Seite 490-502 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lecomte, Sara [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antibodies, Monoclonal |
|---|
| Anmerkungen: |
Date Completed 06.02.2023 Date Revised 19.11.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1182/blood.2022017097 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM348369018 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM348369018 | ||
| 003 | DE-627 | ||
| 005 | 20231226040015.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood.2022017097 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1161.xml |
| 035 | |a (DE-627)NLM348369018 | ||
| 035 | |a (NLM)36322928 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lecomte, Sara |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Therapeutic activity of GARP:TGF-β1 blockade in murine primary myelofibrosis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.02.2023 | ||
| 500 | |a Date Revised 19.11.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
| 520 | |a Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-β1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-β1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-β1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-β1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-β1 activation by GARP-expressing cells. GARP:TGF-β1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-β1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-β1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 700 | 1 | |a Devreux, Julien |e verfasserin |4 aut | |
| 700 | 1 | |a de Streel, Grégoire |e verfasserin |4 aut | |
| 700 | 1 | |a van Baren, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Havelange, Violaine |e verfasserin |4 aut | |
| 700 | 1 | |a Schröder, David |e verfasserin |4 aut | |
| 700 | 1 | |a Vaherto, Noora |e verfasserin |4 aut | |
| 700 | 1 | |a Vanhaver, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Vanderaa, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Dupuis, Noémie |e verfasserin |4 aut | |
| 700 | 1 | |a Pecquet, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Coulie, Pierre G |e verfasserin |4 aut | |
| 700 | 1 | |a Constantinescu, Stefan N |e verfasserin |4 aut | |
| 700 | 1 | |a Lucas, Sophie |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 141(2023), 5 vom: 02. Feb., Seite 490-502 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
| 773 | 1 | 8 | |g volume:141 |g year:2023 |g number:5 |g day:02 |g month:02 |g pages:490-502 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2022017097 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 141 |j 2023 |e 5 |b 02 |c 02 |h 490-502 | ||