Generics in information structure: exceptions versus counterexamples

Why do we hold on to generic beliefs that serve explanations and our way of understanding the world, even if they run counter to facts or observational evidence with which they are incompatible? It often makes rational sense NOT to revise one’s belief, even if counterexamples abound, relegating them to the harmless status of exceptions, rather than disconfirming facts. Investigating the focus/background structure arising from the interaction between aspectual adverbs, tense and bare plurals requires an interface of all modules of grammar—the Information Structure—at which the content of statements with bare plurals in discourse can be determined in context and epistemological differences between exceptions and counterexamples are accounted for. Generic information is persistent in recalcitrant situations, because its explanatory force is “immunized” against counterevidence. “Immunization” of information against counterevidence is a new theoretical semantic concept given precise content in an epistemologically flavored semantics of generics.Pourquoi nous accrochons-nous aux croyances génériques qui nous servent à expliquer et comprendre le monde, même lorsqu’elles vont à l’encontre de faits ou d’observations évidentes avec lesquelles elles sont contradictoires ? Il est souvent rationnel de ne pas corriger ses croyances, même si les contre-exemples abondent, en reléguant ces derniers au statut d’exceptions anodines qui n’infirmeront pas les faits. L’étude de la structure focus/arrière-plan qui résulte de l’interaction entre les adverbes aspectuels, le temps et les pluriels nus nécessite une interface de tous les modules de la grammaire – la Structure Informationnelle – dans laquelle le contenu des énoncés avec pluriels nus peut être déterminé en contexte, et dans laquelle sont expliquées les différences épistémologiques entre exceptions et contre-exemples. Les informations génériques persistent dans les situations récalcitrantes parce que leur force explicative est « immunisée » contre les preuves contraires. Cette « immunisation » de l’information est un nouveau concept sémantique théorique dont nous précisons le contenu dans une sémantique des génériques qui emprunte à l’épistémologie

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