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 happened in the mid-1990s? The coupled ocean-atmosphere processes behind climate-induced ecosystem changes in the Northeast Atlantic and the Mediterranean

Northeast Atlantic marine ecosystems such as the Bay of Biscay, Celtic Sea, English Channel, Subpolar Gyre region, Icelandic waters and North Sea as well as the Mediterranean Sea show concomitant ‘regime shift’-like changes around the mid-1990s, which involved all biota of the pelagial: phytoplankton, zooplankton, pelagic fish assemblages, demersal fish assemblages and top predators. These shifts were caused by complex ocean-atmosphere interactions initiating large-scale changes in the strength and direction of the current systems, that move water masses around the North Atlantic, and involved the North Atlantic Oscillation (NAO), the Atlantic Meridional Overturning Circulation (AMOC), and the subpolar gyre (SPG). The contractions and expansions of the SPG and fluctuations of the Atlantic Multidecadal Oscillation (AMO) play a key role in these complex processes. Small pelagic fish population trends were the sentinels of these changes in the mid-1990s in the ecosystems under investigation

Climate change complicates efforts to ensure survival and recovery of St. Lawrence Estuary beluga

This study was funded by the Species at Risk programme of Fisheries and Oceans Canada.Decades after a ban on hunting, and despite focused management interventions, the endangered St. Lawrence Estuary (SLE) beluga (Delphinapterus leucas) population has failed to recover. We applied a population viability analysis to simulate the responses of the SLE beluga population across a wide range of variability and uncertainty under current and projected changes in environmental and climate-mediated conditions. Three proximate threats to recovery were explored: ocean noise; contaminants; and prey limitation. Even the most optimistic scenarios failed to achieve the reliable positive population growth needed to meet current recovery targets. Here we show that predicted effects of climate change may be a more significant driver of SLE beluga population dynamics than the proximate threats we considered. Aggressive mitigation of all three proximate threats will be needed to build the population's resilience and allow the population to persist long enough for global actions to mitigate climate change to take effect.Publisher PDFPeer reviewe

Underwater acoustic impacts of shipping management measures: Results from a social-ecological model of boat and whale movements in the St. Lawrence River Estuary (Canada)

The recovery of whale species at risk requires the implementation of protection measures designed to mitigate the risks posed by various stressors. In the St. Lawrence Estuary (Canada), several whale species are threatened by navigation activities in various ways. Since 2013, seasonal voluntary ship strike mitigation measures, including a speed reduction area (SRA) and a no-go area, were implemented annually and largely adopted by the maritime industry to reduce the risks of lethal collisions with four species of baleen whales. While the endangered St. Lawrence beluga population is unlikely to be subject to collisions with large merchant ships, it is known to be negatively affected by vessel-generated underwater noise. To assess how these protection measures modify the beluga’s soundscape throughout their critical habitat, we implemented an underwater acoustic module within an existing agent-based model (3MTSim) of ship-whale movements and interactions in the St. Lawrence Estuary. We ran multiple simulations for two scenarios 1) without and 2) with the protection measures to compare the level of noise received by belugas before and after 2013. Overall, the simulations showed a statistically-significant 1.6% decrease in the total amount of noise received by belugas in their critical habitat following the implementation of the protection measures. Although slowing down ships reduces instantaneous radiated noise, it also increases the total amount of acoustic energy released in the environment by extending the time spent in the SRA. Accordingly, our simulations showed a 2.4% increase in the cumulative noise from shipping received by beluga in the SRA. Conversely, belugas located in the Upper Estuary, mostly females and calves, i.e., the most valuable individuals experienced a 5.4% reduction in the cumulative received level of shipping noise. Although refinements are required to improve the modelling of noise sources and propagation for finer scale projections in this complex nearshore environment, this agent-based modelling paradigm of 3MTSim proved informative for underwater acoustic impact assessments

Le concept d’approche écosystémique appliqué à l’estuaire du Saint-Laurent (Canada)

Depuis plusieurs années, le concept d’approche écosystémique est avancé mondialement comme une solution possible aux problématiques de gestion liées à la détérioration des écosystèmes marins et de leurs ressources découlant de l’activité humaine, incluant les pêches, le développement industriel, l’aquaculture, etc. Au Canada, le ministère des Pêches et des Océans a développé en 2007 plusieurs initiatives scientifiques régionales afin de tester différents modèles pour l’application d’une telle approche au soutien de la gestion intégrée de diverses activités humaines qui menacent l’intégrité d’un écosystème. L’estuaire maritime du Saint-Laurent, dans l’est canadien, a constitué le cadre d’une de ces initiatives de recherche écosystémique (IRÉ) qui s’est déroulée de 2007 à 2012. L’estuaire est une région de forte production biologique exposée à une vaste gamme de pressions et d’activités humaines pouvant avoir un impact dommageable sur son intégrité et son utilisation durable. Lors d’ateliers de consultations incluant la participation à la fois de scientifiques et des principaux gestionnaires de cette région, deux priorités communes ont été retenues pour la mise en oeuvre de cette IRÉ, soit : (1) espèces fourragères responsables de la présence du rorqual bleu dans l’estuaire maritime du Saint-Laurent et (2) caractérisation des habitats fréquentés par le béluga du Saint-Laurent. L’objectif général de l’IRÉ de l’estuaire du Saint-Laurent était de développer un cadre opérationnel pour la coordination et l’intégration de projets existants ou des suivis en cours avec des nouveaux projets afin de fournir des informations et des avis scientifiques intégrés (application de l’approche écosystémique) reliés aux deux priorités choisies. Les deux thèmes ont abouti à une évaluation scientifique intégrée documentée dans des avis à caractère écosystémique sur plusieurs enjeux de gestion et objectifs de conservation à l’échelle de l’écosystème. Les résultats ont généré de l’information très pertinente à la gestion du parc marin Saguenay–Saint-Laurent, la mise en oeuvre de plans de rétablissement d’espèces en péril (béluga, rorqual bleu) et l’établissement attendu d’une zone de protection marine dans la région. L’objectif du manuscrit est de décrire les éléments qui ont justifié le choix de l’estuaire maritime du Saint-Laurent comme aire d’étude et de présenter la mise en œuvre et certains résultats intégrateurs de l’initiative de recherche écosystémique dans cette région.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author