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

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

What determines demand for European Union referendums?

Notwithstanding elite opposition to referendums as inconsistent with theories of representative democracy, the 27-nation European Election Study finds that 63 per cent of EU citizens want a vote on EU treaties. One explanation is that the majority want more popular participation in politics; another is that referendums are demanded by those negative about the performance of their governors at national and EU levels; a third is that demand is higher where referendums are part of the national context. Multi-level statistical analysis shows greater support for the hypotheses that citizens dissatisfied with government performance are more likely to want referendums to check their governors and that national context matters. However, dissatisfied EU citizens are a minority; most who endorse EU referendums are actually pro-EU. This lowers the risk of defeat if the EU consulted its citizens in a pan-European referendum

New Method for Modeling Connective-Tissue Cell Migration: Improved Accuracy on Motility Parameters

Mathematical models of cell migration based on persistent random walks have been successfully applied to describe the motility of several cell types. However, the migration of slowly moving connective-tissue cells, such as fibroblasts, is difficult to observe experimentally and difficult to describe theoretically. We identify two primary sources of this difficulty. First, cells such as fibroblasts tend to migrate slowly and change shape during migration. This makes accurate determination of cell position difficult. Second, the cell population is considerably heterogeneous with respect to cell speed. Here we develop a method for fitting connective-tissue cell migration data to persistent random walk models, which accounts for these two significant sources of error and enables accurate determination of the cell motility parameters. We demonstrate the usefulness of this method for modeling both isotropic cell motility and biased cell motility, where the migration of a population of cells is influenced by a gradient in a surface-bound adhesive peptide. This method can discern differences in the motility of populations of cells at different points along the peptide gradient and can therefore be used as a tool to quantify the effects of peptide concentration and gradient magnitude on cell migration

Strained diphosphines built upon a calix[4]arene skeleton. Synthesis of a highly active norbornene polymerization catalyst

The complexes cis-P,P'-(eta(5)-cylopentadienyl)-{5, 17-dibromo-11, 23-bis(diphenylphosphino)-25,26,27,28-tetrapropoxy-calix[4]arene}nickle(II) tetrafluoroborate (1) and dibromo-{5, 17-dibromo-11 23-bis(diphenylphosphino)- 25,26,27,28-tetrapropoxycalix[4]arene}nickel(II) (2), both of which contain a constrained chelating disphosphine, were evaluated for the polymerization of norbornene. Combined with methylaluminoxane, they result in remarkably, active systems for the production of high-molar-mass vinyl-type polynorbornene. Turnover frequencies of up to 7.5 x 10(5) mol(NBE) . mol(Ni)(-1) . h(-1) are observed. A plausible explanation for their high performances relies on a periodic P-Ni-P bite angle enlargement that temporarily increases the steric hindrance about the catalytic centre, which in turn favours the insertion steps

Localization of B11 in early endosomes and lysosomes.

<p>A) B11 internalization into early endosomes was followed by co-localization experiments using an anti-FLAG antibody (green) and the EEA1 protein, a marker of early endosome compartment, and imaged with the anti-EEA1 antibody (red). As shown in the merged images the two proteins co-localized (yellow) within the early endosome vesicles at 30 minutes. B) B11 trafficking into the lysosomes was followed by co-localization experiments using the anti-FLAG antibody (green) and anti-LAMP1 (red). Co-localization can be observed in the merged view (yellow) at 60 minutes.</p

Amino acid sequences for Loop BC variants.

<p>Amino acid sequences for Loop BC variants.</p