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.

Survival following very preterm birth is associated with cognitive and behavioral sequelae, which may have identifiable neural correlates. Many survivors of modern neonatal care in the 1990s are now young adults and the evolution of MRI findings into adult life has rarely been evaluated. We have investigated a cohort of 19-year-old adolescents without severe impairments born between 22 and 26 weeks of gestation in 1995 (extremely preterm: EP). Using T2 data derived from magnetic resonance imaging we investigate differences between the brains of 46 EP participants (n = 46) and the brains of a group of term-born controls (n = 20). Despite EP adolescents having significantly reduced gray and white matter volumes, the composition of these tissues, assessed by both single and multi-component relaxometry, appears to be unrelated to either preterm status or gender. This may represent either insensitivity of the imaging technique or reflect that there are only subtle differences between EP subjects and their term-born peers.