| Autor: |
J. M. Vicencio, R. Evans, R. Green, Z. An, J. Deng, C. Treacy, R. Mustapha, J. Monypenny, C. Costoya, K. Lawler, K. Ng, K. De-Souza, O. Coban, V. Gomez, J. Clancy, S. H. Chen, A. Chalk, F. Wong, P. Gordon, C. Savage, C. Gomes, T. Pan, G. Alfano, L. Dolcetti, J. N. E. Chan, F. Flores-Borja, P. R. Barber, G. Weitsman, D. Sosnowska, E. Capone, S. Iacobelli, D. Hochhauser, J. A. Hartley, M. Parsons, J. N. Arnold, S. Ameer-Beg, S. A. Quezada, Y. Yarden, G. Sala, T. Ng |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 13, Iss 3, Pp 1-14 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-022-04701-3 |
| Popis: |
Abstract Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink