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

Structural analysis along the Ouray fault, southwestern Colorado: implications for the kinematic development of the late Paleozoic Ancestral Rocky Mountains

2021 Fall.Includes bibliographical references.The Ouray fault in southwest Colorado provides insight into the geometry and kinematics of deformation during the formation of the late Paleozoic Ancestral Rocky Mountains (ARM). The Ouray fault strikes WNW-ESE and dips subvertically to steeply south, juxtaposing the Paleoproterozoic Uncompahgre Group on the south side against Mississippian-Pennsylvanian strata on the north side. Kinematic data from the Ouray fault, adjacent small-scale faults, the observed offset, and folds in Paleozoic strata indicate that the Ouray fault records sinistral transpression. Using the average 15° W-plunging slickenlines from the principal slip plane, we estimate the total oblique sinistral displacement of the fault to be ~600 to 800 m. The uniformly overlapping Mesozoic strata atop the projected trace of the Ouray fault indicate that the fault is a preserved ARM structure not reactivated during the Laramide orogeny. The Ouray fault is oriented subparallel to the Uncompahgre Group bedding and follows the weaker Uncompahgre phyllite for most of its length, suggesting the preexisting structures within the Uncompahgre Group greatly influenced the orientation of the Ouray fault. N-S- to NW-SE-striking joints and quartz veins in all geologic units spanning the Paleoproterozoic to the Cenozoic postdate slip on the Ouray fault and likely formed during Cenozoic magmatism. A sample of calcite from the principal slip plane of the Ouray fault yielded a U-Pb date of 39.3 ± 6.2 Ma. I interpret this date to record resetting by late Eocene hydrothermal fluid flow. The record of strain around the Ouray fault may be representative of the southwestern margin of the Ancestral Uncompahgre uplift in Colorado. This study supports recent tectonic models for the ARM system which propose that ARM uplift was driven by NE-SW compression during the Pennsylvanian and Permian periods