Clinical implications of antigen transfer mechanisms from malignant to dendritic cells: Exploiting cross-priming

Expansion and activation of cytolytic T lymphocytes bearing high-affinity T-cell receptors specific for tumor antigens is a major goal of active cancer immunotherapy. Physiologically, T cells receive promitotic and activating signals from endogenous professional antigen-presenting cells (APC) rather than directly from malignant cells. This phenomenon fits with the broader concept of cross-presentation that earlier was demonstrated for minor histocompatibility and viral antigens. Many mechanisms have been found to be capable of transferring antigenic material from malignant cells to APC so that it can be processed and subsequently presented by MHC class I molecules expressed on APC. Dendritic cells (DC) are believed to be the most relevant APC mediating cross-presentation because they can take up antigens from apoptotic, necrotic, and even intact tumor cells. There exist specific molecular mechanisms that ensure this transfer of antigenic material: 1) opsonization of apoptotic bodies; 2) receptors for released heat shock proteins carrying peptides processed intracellularly; 3) Fc receptors that uptake immunocomplexes and immunoglobulins; and 4) pinocytosis. DC have the peculiar capability of reentering the exogenously captured material into the MHC class I pathway. Exploitation of these pieces of knowledge is achieved by providing DC with complex mixtures of tumor antigens ex vivo and by agents and procedures that promote infiltration of malignant tissue by DC. The final outcome of DC cross-presentation could be T-cell activation (cross-priming) but also, and importantly, T-cell tolerance contingent upon the activation/maturation status of DC. Artificial enhancement of tumor antigen cross-presentation and control of the immune-promoting status of the antigen-presenting DC will have important therapeutic implications in the near future

Measurement of an excess in the yield of J/ψ\psi at very low pTp_{\rm T} in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

We report on the first measurement of an excess in the yield of J/$\psi$ at very low transverse momentum ($p_{\rm T}< 0.3$ GeV/$c$) in peripheral hadronic Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV, performed by ALICE at the CERN LHC. Remarkably, the measured nuclear modification factor of J/$\psi$ in the rapidity range $2.5<y<4$ reaches about 7 (2) in the $p_{\rm T}$ range 0-0.3 GeV/$c$ in the 70-90% (50-70%) centrality class. The J/$\psi$ production cross section associated with the observed excess is obtained under the hypothesis that coherent photoproduction of J/$\psi$ is the underlying physics mechanism. If confirmed, the observation of J/$\psi$ coherent photoproduction in Pb-Pb collisions at impact parameters smaller than twice the nuclear radius opens new theoretical and experimental challenges and opportunities. In particular, coherent photoproduction accompanying hadronic collisions may provide insight into the dynamics of photoproduction and nuclear reactions, as well as become a novel probe of the Quark-Gluon Plasma.Comment: 18 pages, 3 captioned figures, 1 table, authors from page 13, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/191

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88)

Final Report of the Fifth Meeting of Scientific Experts on Fish Stocks in the Central Arctic Ocean

This report provides a summary of the 5th meeting of scientific experts on Fish Stocks in the Central Arctic Ocean (FiSCAO) on October 24‐26, 2017, in Ottawa, Canada. At the request of the 10 parties negotiating on an agreement to prevent unregulated commercial fishing in the High Seas portion of the Central Arctic Ocean (CAO), participants of the 5th FiSCAO meeting were tasked with addressing four Terms of Reference, summarized below: ToR 1. Design a 1‐3 year long mapping program. ToR 2. Design a monitoring program. ToR 3. Identify human, financial, vessel/equipment resources needed for mapping and monitoring. ToR 4. Develop data collection, sharing, and hosting protocols that outline the details of what and how data shall be collected, shared, and hosted for consideration by the Parties. The 5th FiSCAO meeting included scientific representatives from seven states including Canada, the People's Republic of China, the European Union, Iceland, the Republic of Korea, the Kingdom of Norway and the United States of America. The meeting also included representatives from the International Council for the Exploration of the Sea (ICES), the North Pacific Marine Science Organization (PICES) and the Arctic Council’s Protection of the Arctic Marine Environment (PAME) and Conservation of Arctic Flora and Fauna (CAFF) working groups. The report summarizes the elements for collecting baseline data (i.e., a mapping program) in the high seas CAO to achieve the goals of documenting species distributions, relative abundances and key ecosystem parameters (ToR 1). The mapping program describes the priority areas to sample, the types of data to collect and possible data collection approaches to employ. Participants emphasized that existing planned surveys are very limited, and that significant dedicated resources will be required to implement the mapping program. The report outlines a strategy for monitoring indicators of fish stocks and ecosystem components (ToR 2). The report includes a list of existing monitoring programs and a prioritized list of indicators to detect environmental change in the high seas CAO. Further refinement of a monitoring program will use information from the mapping program (ToR 1). Participants emphasized the need to begin monitoring as soon as possible and that additional research is required to operationalize monitoring indicators. The report summarizes the preliminary cost estimates (ToR 3) to implement a mapping program to collect data in the high seas portion of the CAO using a vessel of opportunity and in the Pacific Gateway region of the CAO using an independently‐organized survey. Cost implications for the monitoring program and other scientific activities are also listed (e.g., data analysis, data management). The report includes a draft data sharing policy as the foundation for a future data sharing protocol, including the technical specifications for data sharing (ToR 4). The development of the data sharing protocol will require negotiation and legal review among the participating states. A data management and data sharing pilot study on a CAO fish database is suggested to test a framework

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio

Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at s=0.9\sqrt{s}=0.9, 2.76 and 7 TeV

Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at $\sqrt{s}=0.9$, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with $p_{\rm T}\geq0.5$ GeV/c in $|\eta|\leq0.8$. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity ($N_{\rm ch}$) is reported for events with different $p_{\rm T}$ scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low $N_{\rm ch}$, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean $p_{\rm T}$ with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16, published version, figures from http://aliceinfo.cern.ch/ArtSubmission/node/308

Dendritic Cells Take up and Present Antigens from Viable and Apoptotic Polymorphonuclear Leukocytes

Dendritic cells (DC) are endowed with the ability to cross-present antigens from other cell types to cognate T cells. DC are poised to meet polymorphonuclear leukocytes (PMNs) as a result of being co-attracted by interleukin-8 (IL-8), for instance as produced by tumor cells or infected tissue. Human monocyte-derived and mouse bone marrow-derived DC can readily internalize viable or UV-irradiated PMNs. Such internalization was abrogated at 4°C and partly inhibited by anti-CD18 mAb. In mice, DC which had internalized PMNs containing electroporated ovalbumin (OVA) protein, were able to cross-present the antigen to CD8 (OT-1) and CD4 (OT-2) TCR-transgenic T cells. Moreover, in humans, tumor cell debris is internalized by PMNs and the tumor-cell material can be subsequently taken up from the immunomagnetically re-isolated PMNs by DC. Importantly, if human neutrophils had endocytosed bacteria, they were able to trigger the maturation program of the DC. Moreover, when mouse PMNs with E. coli in their interior are co-injected in the foot pad with DC, many DC loaded with fluorescent material from the PMNs reach draining lymph nodes. Using CT26 (H-2d) mouse tumor cells, it was observed that if tumor cells are intracellularly loaded with OVA protein and UV-irradiated, they become phagocytic prey of H-2d PMNs. If such PMNs, that cannot present antigens to OT-1 T cells, are immunomagnetically re-isolated and phagocytosed by H-2b DC, such DC productively cross-present OVA antigen determinants to OT-1 T cells. Cross-presentation to adoptively transferred OT-1 lymphocytes at draining lymph nodes also take place when OVA-loaded PMNs (H-2d) are coinjected in the footpad of mice with autologous DC (H-2b). In summary, our results indicate that antigens phagocytosed by short-lived PMNs can be in turn internalized and productively cross-presented by DC