Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21445-4
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Funding
- Breast Cancer Research Foundation [BCRF-20-08]
- Instituto de Salud Carlos III [AC15/00062]
- EC
- FEDER, Instituto de Salud Carlos III [CB16/12/00449, PI19/01181]
- Asociacion Espanola Contra el Cancer (AECC)
- Spanish Government (Juan de la Cierva Formacion) [FJCI-2017-34900]
- Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) - BBVA Foundation [89/2017]
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Immunotherapy has shown promise in cancer treatment, with T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) being potential tools for this approach. This study reveals that disruption of interferon-gamma signaling, including downregulation of JAK2, in cancer cells confers resistance to T cell-mediated cytotoxicity directed against HER2, highlighting a potential mechanism for resistance to T cell-engaging therapies.
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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