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

Test of Grazing Compensation and Optimization of Crested Wheatgrass Using a Simulation Model

We developed a simulation model based on tiller population processes to test grazing compensation and optimization in crested wheatgrass (Agropyron desertorum (Fisch. ex Link) Schult.). Model functions describing tiller dynamics and growth were derived from field observations in west-central Utah. Predicted tiller growth and new tiller production following defoliation were verified against additional data from the same site; total production was validated against a 30-year-old data set from a different site. We then simulated 2 grazing experiments. First, grazing compensation was determined as a function of the timing of a single defoliation during the growing season. Response variables included tiller density, plot growth rates, standing crop, and seasonal production. Second, grazing optimization, a combination of grazing frequency and intensity that increases primary production above that of ungrazed plants, was assessed by the systematic variation of these defoliation parameters under simulated dry, average, and wet winters (September-May). Results of the first experiment indicated that compensation depended mainly on the timing of defoliation, presumably because of phenological constraints to regrowth and the short growing season in this cold-desert region. Overcompensation only occurred when plants were defoliated before the traditional start of the grazing season. Although defoliation increased tiller growth rates, the second experiment failed to reveal an optimum combination of defoliation frequency and intensity resulting in maximum biomass production except after a dry winter. Results from the second experiment indicated that implementing intensive rotational grazing systems will seldom increase crested wheatgrass production in these cold-desert systems

Prescribed Sheep Grazing to Suppress Spotted Knapweed on Foothill Rangeland

Spotted knapweed (Centaurea biebersteinii DC.) is a perennial, invasive forb that infests millions of hectares of private and public rangelands in western North America. Previous research indicates that domestic sheep (Ovis aries) readily graze spotted knapweed, but landscape-scale prescriptive grazing of spotted knapweed has not been studied. We quantified the diets and forage utilization of a ewe-lamb band (about 800 ewes and 1 120 lambs) that prescriptively grazed spotted knapweed-infested foothill rangeland in western Montana in the summers of 2003 and 2004. In mid-June or mid-July, sheep grazed light and moderate infestations of spotted knapweed (13% and 36% of vegetative composition, respectively). Nutritive quality of sheep diets was similar to sheep grazing uninfested rangeland, and sheep exhibited few forage preferences or avoidances. Sheep diets averaged 64% spotted knapweed in the moderate infestation and 26% in the light infestation. Sheep in the light infestation ate fewer graminoids in June than July (17% vs. 55% of their diet, respectively; P=0.04), whereas sheep in the moderate infestation ate fewer graminoids in July (45% in June vs. 20% in July; P = 0.09). In the moderate infestation, relative utilization of spotted knapweed was greater in July than June (50% vs. 35%, respectively; P50.04), but averaged 46% in the light infestation. Previous research suggests that these levels of relative utilization may make herbicide application uneconomical. Relative utilization of graminoids was light in both infestations (15% in June or 31% in July). Our results indicate that sheep can prescriptively graze light or moderate spotted knapweed infestations in either June or July. Sheep consumption and relative utilization of graminoids will be less if light infestations are grazed in June rather than July. In moderate infestations, sheep will eat fewer graminoids and utilize spotted knapweed more heavily when grazed in July rather than June. The Rangeland Ecology & Management archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform August 202