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

Modeling top-down and bottom-up drivers of a regime shift in invasive aquatic plant stable states

CITATION: Strange, E. F., et al. 2019. Modeling top-down and bottom-up drivers of a regime shift in invasive aquatic plant stable states. Frontiers in Plant Science, 10:889, doi:10.3389/fpls.2019.00889.The original publication is available at https://www.frontiersin.orgPublication of this article was funded by the Stellenbosch University Open Access FundThe evidence for alternate stable states characterized by dominance of either floating or submerged plant dominance is well established. Inspired by an existing model and controlled experiments, we conceptually describe a dynamic that we have observed in the field using a simple model, the aim of which was to investigate key interactions of the shift between invasive floating and invasive submerged plant dominance, driven by the rapid decomposition of floating plants as a consequence of herbivory by biological control agents. This study showed that the rate of switch between floating and submerged invasive plant dominance, and the point in time at which the switch occurs, is dependent on the nutrient status of the water and the density of biological control agents on floating plant populations. Therefore, top-down invasive plant biological control efforts using natural enemies can affect systems on a wider scale than the intended agent – plant level, and can be significantly altered by bottom-up changes to the system, i.e., nutrient loading. The implications of this are essential for understanding the multiple roles invasive plants and their control have upon ecosystem dynamics. The results emphasize the importance of multi-trophic considerations for future invasive plant management and offer evidence for new pathways of invasion. The model outputs support the conclusion that, after the shift and in the absence of effective intervention, a submerged invasive stable state will persist.https://www.frontiersin.org/articles/10.3389/fpls.2019.00889/fullPublisher's versio

The abundance of an invasive freshwater snail Tarebia granifera (Lamarck, 1822) in the Nseleni River, South Africa

The invasive freshwater snail Tarebia granifera (Lamarck, 1822) was first reported in South Africa in 1999 and it has become widespread across the country, with some evidence to suggest that it reduces benthic macroinvertebrate biodiversity. The current study aimed to identify the primary abiotic drivers behind abundance patterns of T. granifera, by comparing the current abundance of the snail in three different regions, and at three depths, of the highly modified Nseleni River in KwaZulu-Natal, South Africa. Tarebia granifera was well established throughout the Nseleni River system, with an overall preference for shallow waters and seasonal temporal patterns of abundance. Although it is uncertain what the ecological impacts of the snail in this system are, its high abundances suggest that it should be controlled where possible and prevented from invading other systems in the region

The difference between lipid treated and untreated freshwater fish white muscle tissue samples.

<p>Untreated and lipid treated δ¹³C and C:N values, the difference between them (± SD), and the number of individuals subject to lipid extraction (sample size <i>N</i>), for 18 fish species from the Kavango River.</p

A map of the sample sites on the Upper Zambia, Kavango and Kwando rivers in Namibia.

<p>A map of the sample sites on the Upper Zambia, Kavango and Kwando rivers in Namibia.</p

The fractionation factors (Δδ¹⁵N) estimated using stomach contents analysis of predatory freshwater fish species from the Upper Zambezi, Kavango and Kwando rivers.

<p>N_stomachs are the number of stomachs which contained identified prey items used for this analysis, and δ¹⁵N the isotopic values used for the analyses. The average and standard deviation of Δδ¹⁵N has been calculated from the Δδ¹⁵N per species by river as detailed in the table.</p

The mass proportions (×100) of identified stomach contents for a number of fish species from the Zambezi (Zam), Kavango (Kav) and Kwando (Kwa) rivers, and their <i>δ</i>^<i>15</i><i>N</i>_<i>i</i> values.

<p>The mass proportions (×100) of identified stomach contents for a number of fish species from the Zambezi (Zam), Kavango (Kav) and Kwando (Kwa) rivers, and their <i>δ</i>^<i>15</i><i>N</i>_<i>i</i> values.</p

Re-evaluating the parameter <i>D</i> and constant <i>I</i> for the lipid normalisation equation.

<p>A: the difference in δ¹³C between lipid-extracted and δ¹³C untreated values, and δ¹³C’normalised and δ¹³C untreated values in relation to the C:N ratio of white muscle tissue of freshwater fishes. This is compared with the lipid normalisation equation estimated by McConnaughey and McRoy [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178047#pone.0178047.ref022" target="_blank">22</a>] and re-evaluated by Kiljunen et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178047#pone.0178047.ref024" target="_blank">24</a>]. B: The δ¹³C lipid extracted and δ¹³C’ normalised values in relation to the δ¹³C untreated values. This illustrates the accuracy of the amended normalisation equation in calculating δ¹³C’ values which coincide with the δ¹³C lipid extracted samples.</p