Human Tumour Immune Evasion via TGF-β Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity

Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-β. Release from TGF-β-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-β dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-β dependent inhibition upon autologous NK cells ex vivo. TGF-β antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-β treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-β blockade and both anti-TGF-β antibodies and a small molecule inhibitor of TGF-β signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-β blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity

Asymmetric O–H insertion reaction of carbenoids catalyzed by chiral bicyclo bisoxazoline copper(I) and (II) complexes

International audienceChiral copper(I) and (II)-bicyclobisoxazoline complexes were found to catalyze the insertion of α-diazocarbonyl compounds into O–H bonds of alcohols. The insertion reactions of various α-diazopropionates proceeded with moderate yields (40–90%) and high enantioselectivities (up to 92% and 94% with copper(I) and copper(II)-catalysts, respectively). A predominant effect on the enantiocontrol of the reaction was observed when copper(I) and (II)-catalysts were associated with NaBARF and molecular sieves (4 Å). © 2016 Elsevier Lt

Emulsion-Based Delivery Systems for Tributyrin, a Potential Colon Cancer Preventative Agent

Tributyrin, a short-chain triglyceride oil used as a food additive, has been reported to be a potential preventive agent against colon cancer. The purpose of this study was to develop tributyrin delivery systems based on food-grade oil-in-water emulsions that could potentially be incorporated into foods. Emulsions containing only tributyrin as the lipid phase were highly unstable to droplet growth due to Ostwald ripening (OR) because of the relatively high water solubility of this low molecular weight triacylglycerol. The stability of the emulsions to OR could be greatly improved by incorporating \u3eor=15-25% corn oil (a food-grade oil with a low water solubility) into the lipid phase. In addition, the tendency for droplet sedimentation to occur was reduced because the density contrast between the lipid and water phases was reduced in the mixed tributyrin/corn oil systems. The potential anticarcinogenic ability of the tributyrin emulsions was demonstrated using a cell culture model. Treatments with emulsions containing tributyrin significantly inhibited the viability of HT29 colon carcinoma cells. These results have important implications for the development and testing of nutraceuticals encapsulated in food-grade delivery systems as anticancer agents