13 research outputs found

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Erythropoietin has a restorative effect on the contractility of arteries following experimental hypoxia

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    INTRODUCTION: The aim of this study was to investigate the effect of erythropoietin on vascular contractility using an in vitro model of hypoxia replicating the hypoxic environment of blood vessels and surrounding adipose tissue in obesity. METHODS AND RESULTS: Pharmacological in vitro studies were carried out on small mesenteric arterial segments from male Wistar rats with and without perivascular fat and endothelium. Contractile responses were investigated by wire myography under normoxia, experimental hypoxia ± erythropoietin and l-NNA. Perivascular fat exerted an anticontractile effect which was lost following the induction of experimental hypoxia. Erythropoietin prevented the loss of the anticontractile capacity when vessels were incubated for one hour before the induction of hypoxia or throughout the period of hypoxia; this was found to be independent of the function of perivascular fat, as fat denuded arteries had a similar reduction in contractility (artery no fat + hypoxia vs. artery no fat + hypoxia + erythropoietin). The mechanism by which erythropoietin was exerting its effect was found to be partially endothelium dependent and associated with an increase of nitric oxide bioavailability as nitric oxide synthase inhibition prevented the effect. CONCLUSIONS: Whilst erythropoietin is working downstream from perivascular fat, it is possible that it may be therapeutically useful in obesity when hypoxia and inflammation reduce the normal activity of perivascular fat

    D. Die einzelnen romanischen Sprachen und Literaturen.

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    Financing the Great War: A Class Tax for the Wealthy, Liberty Bonds for All

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    Chapter IV: Teaching Foreign Languages

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