Q1 · BIOLOGY
ArticleOA
Author: Gomez, V ; Weitsman, G ; Vicencio, J M ; Costoya, C ; Ng, T ; Pan, T ; Mustapha, R ; Clancy, J ; Monypenny, J ; Ameer-Beg, S ; Sala, G ; Chalk, A ; An, Z ; Ng, K ; Alfano, G ; Flores-Borja, F ; Lawler, K ; Evans, R ; Coban, O ; Barber, P R ; Gomes, C ; Deng, J ; Treacy, C ; Hochhauser, D ; Green, R ; Yarden, Y ; Chan, J N E ; Hartley, J A ; Quezada, S A ; Dolcetti, L ; Gordon, P ; De-Souza, K ; Sosnowska, D ; Wong, F ; Savage, C ; Iacobelli, S ; Arnold, J N ; Capone, E ; Parsons, M ; Chen, S H
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.