Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy
The high metabolic activity and insufficient perfusion of tumors leads to the acidification of the tumor microenvironment (TME) that may inhibit the antitumor T cell activity. We found that pharmacological inhibition of the acid loader chloride/bicarbonate anion exchanger 2 (Ae2), with 4,4’-diisothi...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/112506 |
| Acesso em linha: | https://hdl.handle.net/10171/112506 |
| Access Level: | acceso abierto |
| Palavra-chave: | Lymphocytes intracellular pH tumor microenvironment AE2 HVCN1 adoptive cell therapy |
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Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapyNavarro-Negredo, F.C. (Flor Cecilia)|||/items/e4384704-3a73-45b3-b5fd-f7a2142bd783Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7bMartín-Otal, C. (Celia)|||/items/083c0c6b-72c5-42ae-a734-97702ba72711Lasarte-Cia, A. (Aritz)|||/items/a2c6eec9-7b5d-49da-86d3-dfee52b636cfGorraiz, M. (Marta)|||/items/2f64930e-4c40-41d8-9a41-8a29266a623fSarrión, P. (Patricia)|||/items/620eae1c-0788-4b5f-8a1e-3250d1cb13a9Llopiz-Khatchikian, D.I. (Diana Isabel)|||/items/3b1cd705-ce8b-4f99-b323-460f59b34f20Repáraz-Pernaut, D. (David)|||/items/c0618bbc-c5af-4ee0-8660-0de8471413e8Varo-Cenarruzabeitia, N. (Nerea)|||/items/18b5a757-44b9-4e23-8a8c-ad907969001fRodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1Lozano-Moreda, T. (Teresa)|||/items/f7df715d-1380-479b-8134-b319df8f0b00Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0cHervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8fLymphocytesintracellular pHtumor microenvironmentAE2HVCN1adoptive cell therapyThe high metabolic activity and insufficient perfusion of tumors leads to the acidification of the tumor microenvironment (TME) that may inhibit the antitumor T cell activity. We found that pharmacological inhibition of the acid loader chloride/bicarbonate anion exchanger 2 (Ae2), with 4,4’-diisothiocyanatostilbene-2,2’-disulfonicacid (DIDS) enhancedCD4+ andCD8+ T cell function upon TCR activation in vitro, especially under low pH conditions. In vivo, DIDS administration delayed B16OVA tumor growth in immunocompetent mice as monotherapy or when combined with adoptive T cell transfer of OVA-specificT cells. Notably, genetic Ae2 silencing in OVA-specificT cells improvedCD4+/CD8+ T cell function in vitro as well as their antitumor activity in vivo. Similarly, genetic modification of OVA-specificT cells to overexpress Hvcn1, a selectiveH+ outward current mediator that prevents cell acidification, significantly improved T cell function in vitro, even at low pH conditions. The adoptive transfer of OVA-specificT cells overexpressing Hvcn1 exerted a better antitumor activity in B16OVA tumor-bearingmice. Hvcn1 overexpression also improved the antitumor activity of CAR T cells specific for Glypican 3 (GPC3) in mice bearing PM299L-GPC3tumors. Our results suggest that preventing intracellular acidification by regulating the expression of acidifier ion channels such as Ae2 or alkalinizer channels like Hvcn1 in tumor-specificlymphocytes enhances their antitumor response by making them more resistant to the acidic TME.Taylor & FrancisDadun. Depósito Académico Digital Universidad de Navarra20222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/112506reponame: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:10171/1125062026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| title |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| spellingShingle |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy Navarro-Negredo, F.C. (Flor Cecilia)|||/items/e4384704-3a73-45b3-b5fd-f7a2142bd783 Lymphocytes intracellular pH tumor microenvironment AE2 HVCN1 adoptive cell therapy |
| title_short |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| title_full |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| title_fullStr |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| title_full_unstemmed |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| title_sort |
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy |
| dc.creator.none.fl_str_mv |
Navarro-Negredo, F.C. (Flor Cecilia)|||/items/e4384704-3a73-45b3-b5fd-f7a2142bd783 Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b Martín-Otal, C. (Celia)|||/items/083c0c6b-72c5-42ae-a734-97702ba72711 Lasarte-Cia, A. (Aritz)|||/items/a2c6eec9-7b5d-49da-86d3-dfee52b636cf Gorraiz, M. (Marta)|||/items/2f64930e-4c40-41d8-9a41-8a29266a623f Sarrión, P. (Patricia)|||/items/620eae1c-0788-4b5f-8a1e-3250d1cb13a9 Llopiz-Khatchikian, D.I. (Diana Isabel)|||/items/3b1cd705-ce8b-4f99-b323-460f59b34f20 Repáraz-Pernaut, D. (David)|||/items/c0618bbc-c5af-4ee0-8660-0de8471413e8 Varo-Cenarruzabeitia, N. (Nerea)|||/items/18b5a757-44b9-4e23-8a8c-ad907969001f Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lozano-Moreda, T. (Teresa)|||/items/f7df715d-1380-479b-8134-b319df8f0b00 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f |
| author |
Navarro-Negredo, F.C. (Flor Cecilia)|||/items/e4384704-3a73-45b3-b5fd-f7a2142bd783 |
| author_facet |
Navarro-Negredo, F.C. (Flor Cecilia)|||/items/e4384704-3a73-45b3-b5fd-f7a2142bd783 Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b Martín-Otal, C. (Celia)|||/items/083c0c6b-72c5-42ae-a734-97702ba72711 Lasarte-Cia, A. (Aritz)|||/items/a2c6eec9-7b5d-49da-86d3-dfee52b636cf Gorraiz, M. (Marta)|||/items/2f64930e-4c40-41d8-9a41-8a29266a623f Sarrión, P. (Patricia)|||/items/620eae1c-0788-4b5f-8a1e-3250d1cb13a9 Llopiz-Khatchikian, D.I. (Diana Isabel)|||/items/3b1cd705-ce8b-4f99-b323-460f59b34f20 Repáraz-Pernaut, D. (David)|||/items/c0618bbc-c5af-4ee0-8660-0de8471413e8 Varo-Cenarruzabeitia, N. (Nerea)|||/items/18b5a757-44b9-4e23-8a8c-ad907969001f Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lozano-Moreda, T. (Teresa)|||/items/f7df715d-1380-479b-8134-b319df8f0b00 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f |
| author_role |
author |
| author2 |
Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b Martín-Otal, C. (Celia)|||/items/083c0c6b-72c5-42ae-a734-97702ba72711 Lasarte-Cia, A. (Aritz)|||/items/a2c6eec9-7b5d-49da-86d3-dfee52b636cf Gorraiz, M. (Marta)|||/items/2f64930e-4c40-41d8-9a41-8a29266a623f Sarrión, P. (Patricia)|||/items/620eae1c-0788-4b5f-8a1e-3250d1cb13a9 Llopiz-Khatchikian, D.I. (Diana Isabel)|||/items/3b1cd705-ce8b-4f99-b323-460f59b34f20 Repáraz-Pernaut, D. (David)|||/items/c0618bbc-c5af-4ee0-8660-0de8471413e8 Varo-Cenarruzabeitia, N. (Nerea)|||/items/18b5a757-44b9-4e23-8a8c-ad907969001f Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1 Lozano-Moreda, T. (Teresa)|||/items/f7df715d-1380-479b-8134-b319df8f0b00 Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Lymphocytes intracellular pH tumor microenvironment AE2 HVCN1 adoptive cell therapy |
| topic |
Lymphocytes intracellular pH tumor microenvironment AE2 HVCN1 adoptive cell therapy |
| description |
The high metabolic activity and insufficient perfusion of tumors leads to the acidification of the tumor microenvironment (TME) that may inhibit the antitumor T cell activity. We found that pharmacological inhibition of the acid loader chloride/bicarbonate anion exchanger 2 (Ae2), with 4,4’-diisothiocyanatostilbene-2,2’-disulfonicacid (DIDS) enhancedCD4+ andCD8+ T cell function upon TCR activation in vitro, especially under low pH conditions. In vivo, DIDS administration delayed B16OVA tumor growth in immunocompetent mice as monotherapy or when combined with adoptive T cell transfer of OVA-specificT cells. Notably, genetic Ae2 silencing in OVA-specificT cells improvedCD4+/CD8+ T cell function in vitro as well as their antitumor activity in vivo. Similarly, genetic modification of OVA-specificT cells to overexpress Hvcn1, a selectiveH+ outward current mediator that prevents cell acidification, significantly improved T cell function in vitro, even at low pH conditions. The adoptive transfer of OVA-specificT cells overexpressing Hvcn1 exerted a better antitumor activity in B16OVA tumor-bearingmice. Hvcn1 overexpression also improved the antitumor activity of CAR T cells specific for Glypican 3 (GPC3) in mice bearing PM299L-GPC3tumors. Our results suggest that preventing intracellular acidification by regulating the expression of acidifier ion channels such as Ae2 or alkalinizer channels like Hvcn1 in tumor-specificlymphocytes enhances their antitumor response by making them more resistant to the acidic TME. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-01-01 2022 2022-01-01 |
| 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 |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/112506 |
| url |
https://hdl.handle.net/10171/112506 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
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 |
| dc.publisher.none.fl_str_mv |
Taylor & Francis |
| publisher.none.fl_str_mv |
Taylor & Francis |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869410904624332800 |
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15,812429 |