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Title:
Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation | Nature Communications
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. 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.
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name:VHIO, Vall dâHebron Barcelona Hospital Campus
address:
name:Tumor Immunology & Immunotherapy Group, VHIO, Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
type:PostalAddress
type:Organization
name:Alena Gros
affiliation:
name:VHIO, Vall dâHebron Barcelona Hospital Campus
address:
name:Tumor Immunology & Immunotherapy Group, VHIO, Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
type:PostalAddress
type:Organization
name:Christian Klein
url:http://orcid.org/0000-0001-7594-7280
affiliation:
name:Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development
address:
name:Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, Schlieren, Switzerland
type:PostalAddress
type:Organization
name:JoaquÃn Arribas
url:http://orcid.org/0000-0002-0504-0664
affiliation:
name:Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus
address:
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
type:PostalAddress
type:Organization
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
address:
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
type:PostalAddress
type:Organization
name:Universitat Autónoma de Barcelona (UAB)
address:
name:Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona (UAB), Bellaterra, Spain
type:PostalAddress
type:Organization
name:Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute)
address:
name:Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
type:PostalAddress
type:Organization
name:Institució Catalana de Recerca i Estudis Avançats (ICREA)
address:
name:Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Tumor Immunology & Immunotherapy Group, VHIO, Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Tumor Immunology & Immunotherapy Group, VHIO, Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, Schlieren, Switzerland
name:Preclinical Research Program, Vall dâHebron Institute of Oncology (VHIO), Vall dâHebron Barcelona Hospital Campus, Barcelona, Spain
name:Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
name:Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona (UAB), Bellaterra, Spain
name:Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
name:Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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