학술논문
Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans
Document Type
article
Author
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
Source
Cell Death and Disease, Vol 13, Iss 3, Pp 1-14 (2022)
Subject
Language
English
ISSN
2041-4889
Abstract
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.