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

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 unfai...

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Autores principales: Arenas, Enrique J., Martínez-Sabadell, Alex, Rius Ruiz, Irene, Román Alonso, Macarena, Escorihuela, Marta, Luque, Antonio, Fajardo, Carlos Alberto, Gros, Alena, Klein, Christian, Arribas, Joaquín
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902842/
https://www.ncbi.nlm.nih.gov/pubmed/33623012
http://dx.doi.org/10.1038/s41467-021-21445-4
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author Arenas, Enrique J.
Martínez-Sabadell, Alex
Rius Ruiz, Irene
Román Alonso, Macarena
Escorihuela, Marta
Luque, Antonio
Fajardo, Carlos Alberto
Gros, Alena
Klein, Christian
Arribas, Joaquín
author_facet Arenas, Enrique J.
Martínez-Sabadell, Alex
Rius Ruiz, Irene
Román Alonso, Macarena
Escorihuela, Marta
Luque, Antonio
Fajardo, Carlos Alberto
Gros, Alena
Klein, Christian
Arribas, Joaquín
author_sort Arenas, Enrique J.
collection PubMed
description 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.
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spelling pubmed-79028422021-03-11 Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation Arenas, Enrique J. Martínez-Sabadell, Alex Rius Ruiz, Irene Román Alonso, Macarena Escorihuela, Marta Luque, Antonio Fajardo, Carlos Alberto Gros, Alena Klein, Christian Arribas, Joaquín Nat Commun Article 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. Nature Publishing Group UK 2021-02-23 /pmc/articles/PMC7902842/ /pubmed/33623012 http://dx.doi.org/10.1038/s41467-021-21445-4 Text en © 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/.
spellingShingle Article
Arenas, Enrique J.
Martínez-Sabadell, Alex
Rius Ruiz, Irene
Román Alonso, Macarena
Escorihuela, Marta
Luque, Antonio
Fajardo, Carlos Alberto
Gros, Alena
Klein, Christian
Arribas, Joaquín
Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title_full Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title_fullStr Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title_full_unstemmed Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title_short Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
title_sort acquired cancer cell resistance to t cell bispecific antibodies and car t targeting her2 through jak2 down-modulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902842/
https://www.ncbi.nlm.nih.gov/pubmed/33623012
http://dx.doi.org/10.1038/s41467-021-21445-4
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