Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment.

ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.

'Green incubation': avian offspring benefit from aromatic nest herbs through improved parental incubation behaviour.

Development of avian embryos requires thermal energy, usually from parents. Parents may, however, trade off catering for embryonic requirements against their own need to forage through intermittent incubation. This dynamically adjusted behaviour can be affected by properties of the nest. Here, we experimentally show a novel mechanism by which parents, through incorporation of aromatic herbs into nests, effectively modify their incubation behaviour to the benefit of their offspring. Our study species, the European starling, includes in its nest aromatic herbs which promote offspring fitness. We provided wild starlings with artificial nests including or excluding the typically selected fresh herbs and found strong support for our prediction of facilitated incubation. Herb effects were not explained by thermal changes of the nests per se, but by modified parental behaviours. Egg temperatures and nest attendance were higher in herb than herbless nests, egg temperatures dropped less frequently below critical thresholds and parents started their active day earlier. These effects were dynamic over time and particularly strong during early incubation. Incubation period was shorter in herb nests, and nestlings were heavier one week after hatching. Aromatic herbs hence influenced incubation in beneficial ways for offspring, possibly through pharmacological effects on incubating parents.