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

Uncertainty in global groundwater storage estimates in a T

Groundwater is a finite resource under continuous external pressures. Current unsustainable groundwater use threatens the resilience of aquifer systems and their ability to provide a long‐term water source. Groundwater storage is considered to be a factor of groundwater resilience, although the extent to which resilience can be maintained has yet to be explored in depth. In this study, we assess the limit of groundwater resilience in the world's largest groundwater systems with remote sensing observations. The Total Groundwater Stress (TGS) ratio, defined as the ratio of total storage to the groundwater depletion rate, is used to explore the timescales to depletion in the world's largest aquifer systems and associated groundwater buffer capacity. We find that the current state of knowledge of large‐scale groundwater storage has uncertainty ranges across orders of magnitude that severely limit the characterization of resilience in the study aquifers. Additionally, we show that groundwater availability, traditionally defined as recharge and redefined in this study as total storage, can alter the systems that are considered to be stressed versus unstressed. We find that remote sensing observations from NASA's Gravity Recovery and Climate Experiment can assist in providing such information at the scale of a whole aquifer. For example, we demonstrate that a groundwater depletion rate in the Northwest Sahara Aquifer System of 2.69 ± 0.8 km(3)/yr would result in the aquifer being depleted to 90% of its total storage in as few as 50 years given an initial storage estimate of 70 km(3)

Rotating micro-structures in Antarctic cold basal ice: implications for glacier flow and its interpretation

Structural analyses were conducted in the basal zone of an Antarctic glacier. The studied basal ice sequence was retrieved from a 20-m-long subglacial tunnel dug at the margin of the glacier and is at the temperature of -17°C. For the first time, rotating clast systems embedded within debris-rich ice were thin-sectioned using specially designed cutting techniques. The observed structures reflect the occurrence of pervasive shearing at the base of the glacier, and can be used as shear sense indicators. In addition, some of these structures provide evidence for the presence of thin liquid films at the time of formation despite the marked freezing temperature of the ice. It is showed here that cautious analysis of deformation structures present in debris-bearing ice may bring insights not only into the flow dynamics of the embedding matrix, but also into the behaviour of the interstitial fluid network at the base of cold glaciers and ice sheets. © 2009 Springer-Verlag.SCOPUS: ar.jinfo:eu-repo/semantics/publishe