Details

Autor(en) / Beteiligte

• Vicencio, J M
• Evans, R
• Green, R
• An, Z
• Deng, J
• Treacy, C
• Mustapha, R
• Monypenny, J
• Costoya, C
• Lawler, K
• Ng, K
• De-Souza, K
• Coban, O
• Gomez, V
• Clancy, J
• Chen, S H
• Chalk, A
• Wong, F
• Gordon, P
• Savage, C
• Gomes, C
• Pan, T
• Alfano, G
• Dolcetti, L
• Chan, J N E
• Flores-Borja, F
• Barber, P R
• Weitsman, G
• Sosnowska, D
• Capone, E
• Iacobelli, S
• Hochhauser, D
• Hartley, J A
• Parsons, M
• Arnold, J N
• Ameer-Beg, S
• Quezada, S A
• Yarden, Y
• Sala, G
• Ng, T

Titel

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Ist Teil von

• Cell death & disease, 2022-03, Vol.13 (3), p.274-14, Article 274

Ort / Verlag

England: Springer Nature B.V

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.