Cells have the ability to communicate with their immediate and distant neighbors through the release of extracellular vesicles (EVs). EVs facilitate intercellular signaling through the packaging of specific cargo in all type of cells, and perturbations of EV biogenesis, sorting, release and uptake is the basis of a number of disorders. In this review, we summarize recent advances of the complex roles of the sphingolipid ceramide and lysosomes in the journey of EV biogenesis to uptake.

Autophagy is a fundamental catabolic process essential for the maintenance of cellular and tissue homeostasis, as well as directly contributing to the control of invading pathogens. Unsurprisingly, this process becomes critical in supporting cellular dysregulation that occurs in cancer, particularly the tumor microenvironments and their immune cell infiltration, ultimately playing a role in responses to cancer therapies. Therefore, understanding “cancer autophagy” could help turn this cellular waste-management service into a powerful ally for specific therapeutics. For instance, numerous regulatory mechanisms of the autophagic machinery can contribute to the anti-tumor properties of oncolytic viruses (OVs), which comprise a diverse class of replication-competent viruses with potential as cancer immunotherapeutics. In that context, autophagy can either: promote OV anti-tumor effects by enhancing infectivity and replication, mediating oncolysis, and inducing autophagic and immunogenic cell death; or reduce OV cytotoxicity by providing survival cues to tumor cells. These properties make the catabolic process of autophagy an attractive target for therapeutic combinations looking to enhance the efficacy of OVs. In this article, we review the complicated role of autophagy in cancer initiation and development, its effect on modulating OVs and immunity, and we discuss recent progress and opportunities/challenges in targeting autophagy to enhance oncolytic viral immunotherapy.

Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation, and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and pro-inflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. In order to gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting: 1) TSP-1-mediated TGF-β1 activation alone (LSKL) or 2) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or to H-IH (PND 1-7 85% O2, PND 7-14 60% O2 and PND 14-21 air with intermittent exposure to 10% O ₂ for 10 min every 4 hours) while either receiving daily s.c. LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1, and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically-relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.