The XMM-SERVS Survey: XMM-Newton Point-source Catalogs for the W-CDF-S and ELAIS-S1 Fields

We present the X-ray point-source catalogs in two of the XMM-Spitzer Extragalactic Representative Volume Survey (XMM-SERVS) fields, W-CDF-S (4.6 deg2) and ELAIS-S1 (3.2 deg2), aiming to fill the gap between deep pencil-beam X-ray surveys and shallow X-ray surveys over large areas. The W-CDF-S and ELAIS-S1 regions were targeted with 2.3 and 1.0 Ms of XMM-Newton observations, respectively; 1.8 and 0.9 Ms exposures remain after flare filtering. The survey in W-CDF-S has a flux limit of 1.0 × 10−14 erg cm−2 s−1 over 90% of its area in the 0.5–10 keV band; 4053 sources are detected in total. The survey in ELAIS-S1 has a flux limit of 1.3 × 10−14 erg cm−2 s−1 over 90% of its area in the 0.5–10 keV band; 2630 sources are detected in total. Reliable optical-to-IR multiwavelength counterpart candidates are identified for ≈89% of the sources in W-CDF-S and ≈87% of the sources in ELAIS-S1. A total of 3129 sources in W-CDF-S and 1957 sources in ELAIS-S1 are classified as active galactic nuclei (AGNs). We also provide photometric redshifts for X-ray sources; ≈84% of the 3319/2001 sources in W-CDF-S/ELAIS-S1 with optical-to-near-IR forced photometry available have either spectroscopic redshifts or high-quality photometric redshifts. The completion of the XMM-Newton observations in the W-CDF-S and ELAIS-S1 fields marks the end of the XMM-SERVS survey data gathering. The ≈12,000 pointlike X-ray sources detected in the whole ≈13 deg2 XMM-SERVS survey will benefit future large-sample AGN studies

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

Distinct TCR signaling pathways drive proliferation and cytokine production in T cells

The physiological basis and mechanistic requirements for a large number of functional immunoreceptor tyrosine-based activation motifs (ITAMs; high ITAM multiplicity) in the complex of the T cell antigen receptor (TCR) and the invariant signaling protein CD3 remain obscure. Here we found that whereas a low multiplicity of TCR-CD3 ITAMs was sufficient to engage canonical TCR-induced signaling events that led to cytokine secretion, a high multiplicity of TCR-CD3 ITAMs was required for TCR-driven proliferation. This was dependent on the formation of compact immunological synapses, interaction of the adaptor Vav1 with phosphorylated CD3 ITAMs to mediate the recruitment and activation of the oncogenic transcription factor Notch1 and, ultimately, proliferation induced by the cell-cycle regulator c-Myc. Analogous mechanistic events were also needed to drive proliferation in response to weak peptide agonists. Thus, the TCR-driven pathways that initiate cytokine secretion and proliferation are separable and are coordinated by the multiplicity of phosphorylated ITAMs in TCR-CD3. © 2013 Nature America, Inc. All rights reserved