Felicitas Bucher

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 pathway represents a potential pharmacological target for those diseases due to its impact on angiogenesis. Surprisingly some STAT3 activators including the IL6 cytokine member oncostatin M (OSM) enhance angiogenesis whereas others like ciliary neurotropic factor (CNTF) reduce it. This study aims to clarify those conflicting effects. In contrast to the antiangiogenic cytokine CNTF, the proangiogenic OSM was able to activate intracellular signaling pathways beyond STAT3 including ERK and AKT. These differences translated into transcriptomic and metabolic shifts. siRNA mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting while enhancing OSMs proangiogenic drive and switching CNTF's antiangiogenic to a proangiogenic response. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown including a compensatory prolonged pSTAT1 activity. In conclusion, the angiogenic effect of STAT3 seems to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways while the STAT3 pathway, predominantly recognized for its proangiogenic phenotypes, reveals novel antiangiogenic potential.

T cell‐derived small extracellular vesicles (sEVs) exhibit anti‐cancer effects. However, their anti‐cancer potential should be reinforced to enhance clinical applicability. Herein, we generated interleukin‐2‐tethered sEVs (IL2‐sEVs) from engineered Jurkat T cells expressing IL2 at the plasma membrane via a flexible linker to induce an autocrine effect. IL2‐sEVs increased the anti‐cancer ability of CD8 + T cells without affecting regulatory T (T reg ) cells and down‐regulated cellular and exosomal PD‐L1 expression in melanoma cells, causing their increased sensitivity to CD8 + T cell‐mediated cytotoxicity. Its effect on CD8 + T and melanoma cells was mediated by several IL2‐sEV‐resident microRNAs (miRNAs), whose expressions were upregulated by the autocrine effects of IL2. Among the miRNAs, miR‐181a‐3p and miR‐223‐3p notably reduced the PD‐L1 protein levels in melanoma cells. Interestingly, miR‐181a‐3p increased the activity of CD8 + T cells while suppressing T reg cell activity. IL2‐sEVs inhibited tumour progression in melanoma‐bearing immunocompetent mice, but not in immunodeficient mice. The combination of IL2‐sEVs and existing anti‐cancer drugs significantly improved anti‐cancer efficacy by decreasing PD‐L1 expression in vivo. Thus, IL2‐sEVs are potential cancer immunotherapeutic agents that regulate both immune and cancer cells by reprogramming miRNA levels.