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

Enrique J. Arenas, Alex Martínez-Sabadell, Irene Rius Ruiz, Macarena Román Alonso, Marta Escorihuela, Antonio Luque, Carlos Alberto Fajardo, Alena Gros, Christian Klein and Joaquín Arribas ()
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Enrique J. Arenas: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Alex Martínez-Sabadell: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Irene Rius Ruiz: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Macarena Román Alonso: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Marta Escorihuela: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Antonio Luque: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus
Carlos Alberto Fajardo: VHIO, Vall d’Hebron Barcelona Hospital Campus
Alena Gros: VHIO, Vall d’Hebron Barcelona Hospital Campus
Christian Klein: Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development
Joaquín Arribas: Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21445-4

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