Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

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• dc.contributor.author Arenas, Enrique J.
• dc.contributor.author Martínez Sabadell, Alex
• dc.contributor.author Rius Ruiz, Irene
• dc.contributor.author Román Alonso, Macarena
• dc.contributor.author Escorihuela, Marta
• dc.contributor.author Luque, Antonio
• dc.contributor.author Fajardo, Carlos Alberto
• dc.contributor.author Gros, Alena
• dc.contributor.author Klein, Christian
• dc.contributor.author Arribas, Joaquín
• dc.date.accessioned 2021-07-05T06:57:58Z
• dc.date.available 2021-07-05T06:57:58Z
• dc.date.issued 2021
• dc.description.abstract Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.
• dc.format.mimetype application/pdf
• dc.identifier.citation Arenas EJ, Martínez-Sabadell A, Rius Ruiz I, Román Alonso M, Escorihuela M, Luque A, Fajardo CA, Gros A, Klein C, Arribas J. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation. Nat Commun. 2021;12(1):1237. DOI: 10.1038/s41467-021-21445-4
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-021-21445-4
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/48072
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2021;12(1):1237
• dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer immunotherapy
• dc.subject.keyword Cancer therapeutic resistance
• dc.title Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion