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

Effects of silicon on <i>Oryza sativa</i> L. seedling roots under simulated acid rain stress

<div><p>Silicon (Si) has an important function in reducing the damage of environmental stress on plants. Acid rain is a serious abiotic stress factor, and Si can alleviate the stress induced by acid rain on plants. Based on these assumptions, we investigated the effects of silicon on the growth, root phenotype, mineral element contents, hydrogen peroxide (H₂O₂) and antioxidative enzymes of rice (<i>Oryza sativa</i> L.) seedling roots under simulated acid rain (SAR) stress. The results showed that the combined or single effects of Si and/or SAR on rice roots depend on the concentration of Si and the pH of the SAR. The combined or single effects of a low or moderate concentration of Si (1.0 or 2.0 mM) and light SAR (pH 4.0) enhanced the growth of rice roots, and the combined effects were stronger than those of the single treatment. A high concentration of Si (4.0 mM) or severe SAR (pH 2.0) exerted deleterious effects. The incorporation of Si (1.0, 2.0 or 4.0 mM) into SAR with pH 3.0 or 2.0 promoted the rice root growth, decreased the H₂O₂ content, increased the Si concentration and the superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and ascorbate peroxidase (APX) activities, maintained the balance of mineral element (K, Ca, Mg, Fe, Zn, and Cu) concentrations in the roots of rice seedlings compared with SAR alone. The alleviatory effects observed with a moderate concentration of Si (2.0 mM) were better than the effects obtained with a low or high concentration of Si (1.0 or 4.0 mM). The observed effects were due to disruptions in the absorption and utilization of mineral nutrients and impacts on the activity of antioxidant enzymes in roots, and this conclusion suggests that the degree of rice root damage caused by acid rain might be attributed to not only acid rain but also the level of Si in the soil.</p></div

SEM of the adaxial epidermis structure in rice seedlings leaves under different treatments: (A-C) rain at pH 6.5; (D-F) SAR at pH 4.0; (G-I) SAR at pH 3.0; (J-L) SAR at pH 2.0; (A, D, G, J) no Si; (B, E, H, K) 2 mM Si; and (C, F, I, L) 4 mM Si.

<p>Symbols: WP: wart-like protuberance. EW: epicuticular wax.</p

Genome‐wide association analyses identify genes modifying age‐at‐onset of Alzheimer’s disease

Background Several studies have attempted to identify genes for age‐at‐onset (AAO) of dementia symptoms in Alzheimer’s disease (AD) through genome‐wide linkage (Daw et al. 1999, Li et al. 2002, Choi et al. 2011) and genome‐wide association studies (Kamboh et al. 2012, Naj et al. 2014). Naj et al. conducted a meta‐analysis of 14 datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) with genotype imputation to HapMap2. Using an expanded set of ADGC cohorts, we re‐examined AAO using higher‐quality genome‐wide imputation data and pooled‐data analysis instead of meta‐analysis to identify novel genetic contributors to AAO of AD. Methods We combined data from 20 non‐Hispanic white prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data were imputed to the Haplotype Reference Consortium (HRC) r1.1 reference panel using the Michigan Imputation Server and consistent quality control applied to each dataset, after which genotype data were merged across datasets using QCTOOL and GTOOL. We performed case‐only association analyses for log10(AAO) using multivariable linear regression with covariate adjustment for sex, cohort, and principal components capturing population substructure, and then conducted analyses conditioning on dosage of APOE ε4 alleles. Variants with P < 10−5 from conditional analyses were re‐analyzed using linear mixed modeling treating cohort as a random effect. Results We used 9,228 AD cases, including 5,307 females (57.4%) with mean (SD) AAO of 74.2(7.7) years. In addition to the APOE region, which reached genome‐wide significance (P < 5 × 10−8), we observed strong novel associations with variants in NTM (encoding neurotrimin) on chr11q25 (rs117589002, P = 1.24 × 10−7) and in an intergenic region on chr3p22.3 (Pmin  = 1.89 × 10−7). Other AAO loci previously identified in the smaller ADGC dataset (Naj et al 2014) remained nominally significant. After adjusting for APOE ε4, thirty‐two regions showed suggestive association (P < 10−5), with chr3p22.3 and NTM remaining the top loci. Chromosome 11q25 includes a known AD linkage region (Blacker et al. 2003). In addition, NTM variation has been found to be correlated with cognitive function tests (Liu et al. 2007) and intelligence (Pan et al. 2010). Conclusions In an expanded ADGC dataset, we confirmed AAO associations in the APOE region and observed evidence for potential novel AD AAO loci including NTM

Effects of Si and SAR on Si content in rice leaves.

<p>n = 3, significantly differences at P < 0.05 were showed with different letter.</p

Effects of Si and SAR on mineral element concentrations in the roots of rice seedlings.

<p>Effects of Si and SAR on mineral element concentrations in the roots of rice seedlings.</p

Images of rice seedling roots under different treatments.

<p>(A-D) no Si; (E-H) 1 mM Si; (I-L) 2 mM Si; (M-P) 4 mM Si; (A, E, I, M) no acid soil; (B, F, J, N) SAR at pH 4; (C, G, K, O) SAR at pH 3; and (D, H, L, P) SAR at pH 2.</p

Effects of Si and SAR on wart-like protuberance (WP) number in rice leaves.

<p>n = 9, significantly differences at P < 0.05 were showed with different letter.</p

Major ions of the SAR (mM).

<p>Major ions of the SAR (mM).</p