IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation
The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathw...
| Autores: | , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/66341 |
| Acceso en línea: | https://hdl.handle.net/10171/66341 |
| Access Level: | acceso abierto |
| Palabra clave: | HSCT IL-2 TGF-β NK cells Myeloid cells Immune reconstitution |
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IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell TransplantationÁlvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205Dunai, C. (Cordelia)|||/items/0e85a6b8-62fb-46d9-8450-dd528b66d1d7Khuat, L.T. (Lam T.)|||/items/dc0231cf-8f40-4dae-8186-bc8cc8d43a17Aguilar, E.G. (Ethan G.)|||/items/55b6679c-87a8-45d9-8159-c9fe3df147a5Barao, I. (Isabel)|||/items/01c9f74e-ac99-4327-a77c-3c168b2010d1Murphy, W.J. (William J.)|||/items/a1db583e-c3c0-4814-9585-f5b7ef75e50eHSCTIL-2TGF-βNK cellsMyeloid cellsImmune reconstitutionThe failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy.Dadun. Depósito Académico Digital Universidad de Navarra20232023-05-2320202020-01-0120202020-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/66341reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/663412026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| title |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| spellingShingle |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation Álvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205 HSCT IL-2 TGF-β NK cells Myeloid cells Immune reconstitution |
| title_short |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| title_full |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| title_fullStr |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| title_full_unstemmed |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| title_sort |
IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation |
| dc.creator.none.fl_str_mv |
Álvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205 Dunai, C. (Cordelia)|||/items/0e85a6b8-62fb-46d9-8450-dd528b66d1d7 Khuat, L.T. (Lam T.)|||/items/dc0231cf-8f40-4dae-8186-bc8cc8d43a17 Aguilar, E.G. (Ethan G.)|||/items/55b6679c-87a8-45d9-8159-c9fe3df147a5 Barao, I. (Isabel)|||/items/01c9f74e-ac99-4327-a77c-3c168b2010d1 Murphy, W.J. (William J.)|||/items/a1db583e-c3c0-4814-9585-f5b7ef75e50e |
| author |
Álvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205 |
| author_facet |
Álvarez, M. (Maite)|||/items/869c2b2f-e806-47ac-8d76-303de908d205 Dunai, C. (Cordelia)|||/items/0e85a6b8-62fb-46d9-8450-dd528b66d1d7 Khuat, L.T. (Lam T.)|||/items/dc0231cf-8f40-4dae-8186-bc8cc8d43a17 Aguilar, E.G. (Ethan G.)|||/items/55b6679c-87a8-45d9-8159-c9fe3df147a5 Barao, I. (Isabel)|||/items/01c9f74e-ac99-4327-a77c-3c168b2010d1 Murphy, W.J. (William J.)|||/items/a1db583e-c3c0-4814-9585-f5b7ef75e50e |
| author_role |
author |
| author2 |
Dunai, C. (Cordelia)|||/items/0e85a6b8-62fb-46d9-8450-dd528b66d1d7 Khuat, L.T. (Lam T.)|||/items/dc0231cf-8f40-4dae-8186-bc8cc8d43a17 Aguilar, E.G. (Ethan G.)|||/items/55b6679c-87a8-45d9-8159-c9fe3df147a5 Barao, I. (Isabel)|||/items/01c9f74e-ac99-4327-a77c-3c168b2010d1 Murphy, W.J. (William J.)|||/items/a1db583e-c3c0-4814-9585-f5b7ef75e50e |
| author2_role |
author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
HSCT IL-2 TGF-β NK cells Myeloid cells Immune reconstitution |
| topic |
HSCT IL-2 TGF-β NK cells Myeloid cells Immune reconstitution |
| description |
The failure of autologous hematopoietic stem cell transplantation (HSCT) has been associated with a profound immunodeficiency that follows shortly after treatment, which renders patients susceptible to opportunistic infections and/or cancer relapse. Thus, given the additional immunosuppressive pathways involved in immune evasion in cancer, strategies that induce a faster reconstitution of key immune effector cells are needed. Natural killer (NK) cells mediate potent anti-tumor effector functions and are the first immune cells to repopulate after HSCT. TGF-β is a potent immunosuppressive cytokine that can impede both the development and function of immune cells. Here, we evaluated the use of an immunotherapeutic regimen that combines low dose of IL-2, an NK cell stimulatory signal, with TGF-β neutralization, in order to accelerate NK cell reconstitution following congenic HSCT in mice by providing stimulatory signals yet also abrogating inhibitory ones. This therapy led to a marked expansion of NK cells and accelerated NK cell maturation. Following HSCT, mature NK cells from the treated recipients displayed an activated phenotype and enhanced anti-tumor responses both in vitro and in vivo. No overt toxicities or adverse effects were observed in the treated recipients. However, these stimulatory effects on NK cell recovery were predicated upon continuous treatment as cessation of treatment led to return to baseline levels and to no improvement of overall immune recovery when assessed at later time-points, indicating strict regulatory control of the NK cell compartment. Overall, this study still demonstrates that therapies that combine positive and negative signals can be plausible strategies to accelerate NK cell reconstitution following HSCT and augment anti-tumor efficacy. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01 2020 2020-01-01 2023 2023-05-23 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
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article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/66341 |
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https://hdl.handle.net/10171/66341 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
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open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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