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

Preparation and optical properties of poly(4-ethynyl-4 `-[N,N-diethylamino]azobenzene-co-phenylacetylene)

A novel soluble functional polyacetylene copolymer (poly(EAAB-co-PA)) of 4-ethynyl-4'-[N,N-diethylamino]azobenzene (EAAB) and phenylacetylene (PA) was synthesized. The structures and properties of the polymers were characterized and evaluated by FTIR, UV-vis, H-1 NMR GPC, optical limiting, and nonlinear optical analyses. The results show that poly(EAAB-co-PA) has the large third-order nonlinear susceptibility, which are two orders of magnitude larger than those of poly(PA) and novel optical limiting property. (c) 2005 Elsevier Ltd. All rights reserved

Formation fluid characteristics and hydrocarbon accumulation in the Dongying sag, Shengli Oilfield

Based on the analysis of geochemical characteristics and distribution of different formation waters, a new origin identification standard was established for the formation water in the Paleogene Shahejie Formation in the Dongying Sag. The migration paths of the connate water expelled from source rocks are similar to those of the hydrocarbons coming from the same rocks, so the geochemical characteristics of the connate water coming from the source rocks can be used as auxiliary indexes to study hydrocarbon migration. Considering fluid pressure and formation water distribution, the Paleogene fluids are divided into three fluid systems: normal-pressure open fluid system, overpressure confined fluid system, and transition fluid system. The differences in hydrocarbon-bearing fluid characteristics, hydrocarbon migration dynamic, hydrocarbon-bearing fluid flow type between these fluid systems were studied. According to characteristics of the hydrocarbon-bearing fluid charging into traps, and formation water drainage pattern, three typical oil accumulation models were classified. In the overpressure confined fluid system, the main oil accumulation mode is high oil saturation fluid entering traps and displacing formation water, and “continuous” reservoirs are prone to form, and fluid oil saturation, fluid charging pressure and fluid seeping conditions affect reservoirs’ oil accumulation extent. In the normal-pressure open fluid system, the main oil accumulation modes include low oil saturation fluids enter a trap while formation water is overflowing out of the trap, and low oil saturation fluids enter a trap while formation water is seeping out of the trap. The amount of hydrocarbon-bearing fluid, fluid oil saturation, trap height, and caprock sealing ability affect reservoir's oil accumulation extent. Key words: formation fluid system, hydrocarbon-bearing fluid, formation water, connate water, non-Darcy flow, hydrocarbon accumulation mode

Tetrahydrofolate Modulates Floral Transition through Epigenetic Silencing.

Folates, termed from tetrahydrofolate (THF) and its derivatives, function as coenzymes in one-carbon transfer reactions and play a central role in synthesis of nucleotides and amino acids. Dysfunction of cellular folate metabolism leads to serious defects in plant development; however, the molecular mechanisms of folate-mediated cellular modifications and physiological responses in plants are still largely unclear. Here, we reported that THF controls flowering time by adjusting DNA methylation-regulated gene expression in Arabidopsis (Arabidopsis thaliana). Wild-type seedlings supplied with THF as well as the high endogenous THF content mutant dihydrofolate synthetase folypoly-Glu synthetase homolog B exhibited significant up-regulation of the flowering repressor of Flowering Wageningen and thereby delaying floral transition in a dose-dependent manner. Genome-wide transcripts and DNA methylation profiling revealed that THF reduces DNA methylation so as to manipulate gene expression activity. Moreover, in accompaniment with elevated cellular ratios between monoglutamylated and polyglutamylated folates under increased THF levels, the content of S-adenosylhomo-Cys, a competitive inhibitor of methyltransferases, was obviously higher, indicating that enhanced THF accumulation may disturb cellular homeostasis of the concerted reactions between folate polyglutamylation and folate-dependent DNA methylation. In addition, we found that the loss-of-function mutant of CG DNA methyltransferase MET1 displayed much less responsiveness to THF-associated flowering time alteration. Taken together, our studies revealed a novel regulatory role of THF on epigenetic silencing, which will shed lights on the understanding of interrelations in folate homeostasis, epigenetic variation, and flowering control in plants