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Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low-seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin-selective peptide, A20, to target αvβ6-positive tumor cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low-affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation factor X, potentially eliminating “off-target” hepatic sequestration in vivo. We engineered an A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines demonstrated significantly increased transduction mediated by αvβ6-targeted variants compared with controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumors. Replication-competent HAdV-D10.A20 demonstrated αvβ6 integrin-selective cell killing in vitro and in vivo. HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions, and reduced off-target uptake. Incorporation of an αvβ6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.

Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.

The extreme chemical and mechanical forces endured by the gastrointestinal tract drive a constant renewal of the epithelial lining. Stem cells of the intestine and stomach, marked by the cell surface receptor Lgr5, preserve the cellular status-quo of their respective tissues through receipt and integration of multiple cues from the surrounding niche. Wnt signalling is a critical niche component for gastrointestinal stem cells and we have previously shown that the Wnt receptor, Frizzled-7 (Fzd7), is required for gastric homeostasis and the function of Lgr5+ intestinal stem cells. Additionally, we have previously shown a requirement for the Wnt target gene Myc in intestinal homeostasis, regeneration and tumourigenesis. However, it is unknown whether Fzd7 or Myc have conserved functions in gastric Lgr5+ stem cells. Here we show that gastric Lgr5+ stem cells do not require Fzd7 or Myc and are able to maintain epithelial homeostasis, highlighting key differences in the way Wnt regulates homeostasis and Lgr5+ stem cells in the stomach compared to the intestinal epithelium. Furthermore, deletion of Myc throughout the epithelium of the gastric antrum has no deleterious effects suggesting therapeutic targeting of Myc in gastric cancer patients will be well tolerated by the surrounding normal tissue.