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

Structure and Magnetic Properties of the Spin-1/2-Based Honeycomb NaNi₂BiO_6‑δ and Its Hydrate NaNi₂BiO_6‑δ·1.7H₂O

We present the structure and magnetic properties of the honeycomb anhydrate NaNi₂BiO_6‑δ and its monolayer hydrate NaNi₂BiO_6‑δ·1.7H₂O, synthesized by deintercalation of the layered α-NaFeO₂-type honeycomb compound Na₃Ni₂BiO₆. The anhydrate adopts ABAB-type oxygen packing and a one-layer hexagonal unit cell, whereas the hydrate adopts an oxygen packing sequence based on a three-layer rhombohedral subcell. The metal-oxide layer separations are 5.7 Å in the anhydrate and 7.1 Å in the hydrate, making the hydrate a quasi 2-D honeycomb system. The compounds were characterized through single crystal diffraction, powder X-ray diffraction, thermogravimetric analysis, and elemental analysis. Temperature-dependent magnetic susceptibility measurements show both to have negative Weiss temperatures (−18.5 and −14.6 K, respectively) and similar magnetic moments (2.21 and 2.26 μ_B/Ni, respectively), though the field-dependent magnetization and heat capacity data suggest subtle differences in their magnetic behavior. The magnetic moments per Ni are relatively high, which we suggest is due to the presence of a mixture of Ni²⁺ and Ni³⁺ caused by oxygen vacancies

Evolutionary models in the Early Triassic marine realm

The relative influences of extrinsic compared to intrinsic drivers of evolutionary change have long been theorized and debated in the fossil record. Ecological recoveries from mass extinction events present records in which to examine these contrasts. Competition in a low diversity world, reproductive strategy, reconstruction of trophic systems and ecological specialization represent possible intrinsic controls on diversification. Feedback between diversity and abundance shifts of marine organisms with biogeochemical cycling and environmental conditions act as extrinsic controls on recovery process and rate. Disentangling these evolutionary pressures is a major challenge for understanding evolutionary recovery from mass extinction.The end-Permian mass extinction (251.88 Ma) represents the largest mass extinction in Earth history and led to an extended recovery interval which lasted the duration of the Early Triassic (~ 4.8 Myr) and beyond. Recent analyses suggest that the survivors of the mass extinction were biased toward organisms with higher metabolic rates that were more resilient against the volatile environmental changes that pervaded the Early Triassic including extreme temperature events, low pH, and low oxygen conditions. We use the Early Triassic recovery of gastropods, echinoids, and ammonoids to examine the processes of taxonomic and ecological evolution in response to, or in spite of, extrinsic environmental perturbations.The case studies of benthic gastropods and echinoids, when compared to pelagic ammonoids reflect similarities and differences in recovery following the end-Permian mass extinction. Gastropods and echinoids exhibit evidence of strong extrinsic environmental limitations which implicate the availability of refugia as a control on recovery. Low initial taxonomic diversity of survivors may have also limited the evolutionary recovery of both clades. Abundant and diverse microgastropod assemblages are interpreted as an adaptation to extreme environmental conditions. The morphological diversity of disarticulated echinoid spines and plates described in the southwestern United States, and examination of phylogenetic ghost lineages hints at a significant “hidden diversity” of Early Triassic echinoids. Ammonoids experienced taxonomic resets but are shown to be resilient to repeated environmental perturbations in the Boreal Ocean over the duration of the Early Triassic. Ammonoids may have adapted to persistent latitudinal temperature gradients and oxygen minimum zones that developed in the Early Triassic ocean basins