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

Primordial Non-Gaussianity

Our current understanding of the Universe is established through the pristine measurements of structure in the cosmic microwave background (CMB) and the distribution and shapes of galaxies tracing the large scale structure (LSS) of the Universe. One key ingredient that underlies cosmological observables is that the field that sources the observed structure is assumed to be initially Gaussian with high precision. Nevertheless, a minimal deviation from Gaussianityis perhaps the most robust theoretical prediction of models that explain the observed Universe; itis necessarily present even in the simplest scenarios. In addition, most inflationary models produce far higher levels of non-Gaussianity. Since non-Gaussianity directly probes the dynamics in the early Universe, a detection would present a monumental discovery in cosmology, providing clues about physics at energy scales as high as the GUT scale

Messengers from the Early Universe: Cosmic Neutrinos and Other Light Relics

The hot dense environment of the early universe is known to have produced large numbers of baryons, photons, and neutrinos. These extreme conditions may have also produced other long-lived species, including new light particles (such as axions or sterile neutrinos) or gravitational waves. The gravitational effects of any such light relics can be observed through their unique imprint in the cosmic microwave background (CMB), the large-scale structure, and the primordial light element abundances, and are important in determining the initial conditions of the universe. We argue that future cosmological observations, in particular improved maps of the CMB on small angular scales, can be orders of magnitude more sensitive for probing the thermal history of the early universe than current experiments. These observations offer a unique and broad discovery space for new physics in the dark sector and beyond, even when its effects would not be visible in terrestrial experiments or in astrophysical environments. A detection of an excess light relic abundance would be a clear indication of new physics and would provide the first direct information about the universe between the times of reheating and neutrino decoupling one second later

Messengers from the Early Universe: Cosmic Neutrinos and Other Light Relics

International audienceThe hot dense environment of the early universe is known to have produced large numbers of baryons, photons, and neutrinos. These extreme conditions may have also produced other long-lived species, including new light particles (such as axions or sterile neutrinos) or gravitational waves. The gravitational effects of any such light relics can be observed through their unique imprint in the cosmic microwave background (CMB), the large-scale structure, and the primordial light element abundances, and are important in determining the initial conditions of the universe. We argue that future cosmological observations, in particular improved maps of the CMB on small angular scales, can be orders of magnitude more sensitive for probing the thermal history of the early universe than current experiments. These observations offer a unique and broad discovery space for new physics in the dark sector and beyond, even when its effects would not be visible in terrestrial experiments or in astrophysical environments. A detection of an excess light relic abundance would be a clear indication of new physics and would provide the first direct information about the universe between the times of reheating and neutrino decoupling one second later

Astro2020 Science White Paper: Primordial Non-Gaussianity

5 pages + references; Submitted to the Astro2020 call for science white papers. This version: fixed author listInternational audienceOur current understanding of the Universe is established through the pristine measurements of structure in the cosmic microwave background (CMB) and the distribution and shapes of galaxies tracing the large scale structure (LSS) of the Universe. One key ingredient that underlies cosmological observables is that the field that sources the observed structure is assumed to be initially Gaussian with high precision. Nevertheless, a minimal deviation from Gaussianityis perhaps the most robust theoretical prediction of models that explain the observed Universe; itis necessarily present even in the simplest scenarios. In addition, most inflationary models produce far higher levels of non-Gaussianity. Since non-Gaussianity directly probes the dynamics in the early Universe, a detection would present a monumental discovery in cosmology, providing clues about physics at energy scales as high as the GUT scale