Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
Arenas, Enrique J. (Centro de Investigación Biomédica en Red de Cáncer)
Martínez-Sabadell, Alex (Vall d'Hebron Institut d'Oncologia)
Rius Ruiz, Irene (Centro de Investigación Biomédica en Red de Cáncer)
Román Alonso, Macarena (Vall d'Hebron Institut d'Oncologia)
Escorihuela, Marta (Vall d'Hebron Institut d'Oncologia)
Luque, Antonio (Vall d'Hebron Institut d'Oncologia)
Fajardo, Carlos Alberto (Vall d'Hebron Institut d'Oncologia)
Gros, Alena (Vall d'Hebron Institut d'Oncologia)
Klein, Christian (Roche Innovation Center Zurich)
Arribas, Joaquín V (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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. Several mechanisms of resistance to T cell-engaging therapies have been described for solid tumors. Here, by using T cell bispecific antibodies and chimeric antigen receptors (CAR) T cells targeting HER2, the authors show that cancer cell intrinsic disruption of interferon-gamma signalling, including downregulation of JAK2, confers resistance to T-cell mediated cytotoxicity.
Ajuts:	Ministerio de Economía y Competitividad AC15/00062 Ministerio de Economía y Competitividad CB16/12/00449 Instituto de Salud Carlos III PI19/01181
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer immunotherapy ; Cancer therapeutic resistance
Publicat a:	Nature communications, Vol. 12 (february 2021) , ISSN 2041-1723

DOI: 10.1038/s41467-021-21445-4
PMID: 33623012

13 p, 2.3 MB

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