1. Academic Validation
  2. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

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

  • Nat Commun. 2021 Feb 23;12(1):1237. doi: 10.1038/s41467-021-21445-4.
Enrique J Arenas  # 1 2 Alex Martínez-Sabadell  # 1 Irene Rius Ruiz 1 2 Macarena Román Alonso 1 Marta Escorihuela 1 Antonio Luque 1 Carlos Alberto Fajardo 3 Alena Gros 3 Christian Klein 4 Joaquín Arribas 5 6 7 8 9
Affiliations

Affiliations

  • 1 Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, 08035, Spain.
  • 2 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, 28029, Spain.
  • 3 Tumor Immunology & Immunotherapy Group, VHIO, Vall d'Hebron Barcelona Hospital Campus, Barcelona, 08035, Spain.
  • 4 Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, Schlieren, 8952, Switzerland.
  • 5 Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, 08035, Spain. [email protected]
  • 6 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, 28029, Spain. [email protected]
  • 7 Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona (UAB), Bellaterra, 08193, Spain. [email protected]
  • 8 Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, 08003, Spain. [email protected]
  • 9 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, 08010, Spain. [email protected]
  • # Contributed equally.
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.

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