Indirect Impact of PD-1/PD-L1 Blockade on a Murine Model of NK Cell Exhaustion

The induction of exhaustion on effector immune cells is an important limiting factor for cancer immunotherapy efficacy as these cells undergo a hierarchical loss of proliferation and cytolytic activity due to chronic stimulation. Targeting PD-1 has shown unprecedented clinical benefits for many cancers, which have been attributed to the prevention of immune suppression and exhaustion with enhanced anti-tumor responses. In this study, we sought to evaluate the role of the PD-1/PD-L1 pathway in murine natural killer (NK) cell activation, function, and exhaustion. In an in vivo IL-2-dependent exhaustion mouse model, neutralization of the PD-1/PD-L1 pathway improved NK cell activation after chronic stimulation when compared to control-treated mice. These cells displayed higher proliferative capabilities and enhanced granzyme B production. However, the blockade of these molecules during long-term in vitro IL-2 stimulation did not alter the progression of NK cell exhaustion (NCE), suggesting an indirect involvement of PD-1/PD-L1 on NCE. Given the expansion of CD8 T cells and regulatory T cells (Tregs) observed upon acute and chronic stimulation with IL-2, either of these two populations could influence NK cell homeostasis after PD-L1/PD-1 therapy. Importantly, CD8 T cell activation and functional phenotype were indeed enhanced by PD-1/PD-L1 therapy, particularly with anti-PD-1 treatment that resulted in the highest upregulation of CD25 during chronic stimulation and granted an advantage for IL-2 over NK cells. These results indicate a competition for resources between NK and CD8 T cells that arguably delays the onset of NCE rather than improving its activation during chronic stimulation. Supporting this notion, the depletion of CD8 T cells reversed the benefits of PD-1 therapy on chronically stimulated NK cells. These data suggest a bystander effect of anti-PD1 on NK cells, resulting from the global competition that exists between NK and CD8 T cells for IL-2 as a key regulator of these cells’ activation. Thus, achieving an equilibrium between these immune cells might be important to accomplish long-term efficacy during anti-PD-1/IL-2 therapy

Conceptual design of the SPL II: A high-power superconducting H−H^- linac at CERN

An analysis of the revised physics needs and recent progress in the technology of superconducting RF cavities have led to major changes in the speci cation and in the design for a Superconducting Proton Linac (SPL) at CERN. Compared with the rst conceptual design report (CERN 2000012) the beam energy is almost doubled (3.5 GeV instead of 2.2 GeV), while the length of the linac is reduced by 40% and the repetition rate is reduced to 50 Hz. The basic beam power is at a level of 45MW and the approach chosen offers enough margins for upgrades. With this high beam power, the SPL can be the proton driver for an ISOL-type radioactive ion beam facility of the next generation (`EURISOL'), and for a neutrino facility based on superbeam C beta-beam or on muon decay in a storage ring (`neutrino factory'). The SPL can also replace the Linac2 and PS Booster in the low-energy part of the CERN proton accelerator complex, improving signi cantly the beam performance in terms of brightness and intensity for the bene t of all users including the LHC and its luminosity upgrade. Decommissioned LEP klystrons and RF equipment are used to provide RF power at a frequency of 352.2 MHz in the lowenergy part of the accelerator. Beyond 90 MeV, the RF frequency is doubled to take advantage of more compact normal-conducting accelerating structures up to an energy of 180 MeV. From there, state-ofthe- art, high-gradient, bulk-niobium superconducting cavities accelerate the beam up to its nal energy of 3.5 GeV. The overall design approach is presented, together with the progress that has been achieved since the publication of the rst conceptual design report

The SPL (II) at CERN, a Superconducting 3.5 GeV H- Linac

A revision of the physics needs and recent progress in the technology of superconducting (SC) RF cavities have triggered major changes in the design of a SC H-linac at CERN. With up to 5MW beam power, the SPL can be the proton driver for a next generation ISOL-type radioactive beam facility (âEURISOLâ) and/or supply protons to a neutrino () facility (conventional superbeam + beta-beam or -factory). Furthermore the SPL can replace Linac2 and the PS booster (PSB), improving significantly the beam performance in terms of brightness, intensity, and reliability for the benefit of all proton users at CERN, including LHC and its luminosity upgrade. Compared with the first conceptual design, the beam energy is almost doubled (3.5GeV instead of 2.2 GeV) while the length is reduced by 40%. At a repetition rate of 50 Hz, the linac reuses decommissioned 352.2MHz RF equipment from LEP in the low-energy part. Beyond 90MeV the RF frequency is doubled, and from 180MeV onwards high-gradient SC bulkniobium cavities accelerate the beam to its final energy of 3.5GeV. This paper presents the overall design approach, together with the technical progress since the first conceptual design in 2000

Genetically-Determined Hyperfunction of the S100B/RAGE Axis Is a Risk Factor for Aspergillosis in Stem Cell Transplant Recipients

Invasive aspergillosis (IA) is a major threat to the successful outcome of hematopoietic stem cell transplantation (HSCT), although individual risk varies considerably. Recent evidence has established a pivotal role for a danger sensing mechanism implicating the S100B/receptor for advanced glycation end products (RAGE) axis in antifungal immunity. The association of selected genetic variants in the S100B/RAGE axis with susceptibility to IA was investigated in 223 consecutive patients undergoing HSCT. Furthermore, studies addressing the functional consequences of these variants were performed. Susceptibility to IA was significantly associated with two distinct polymorphisms in RAGE (-374T/A) and S100B (+427C/T) genes, the relative contribution of each depended on their presence in both transplantation counterparts [patient SNPRAGE, adjusted hazard ratio (HR), 1.97; P = 0.042 and donor SNPRAGE, HR, 2.03; P = 0.047] or in donors (SNPS100B, HR, 3.15; P = 7.8e-4) only, respectively. Functional assays demonstrated a gain-of-function phenotype of both variants, as shown by the enhanced expression of inflammatory cytokines in RAGE polymorphic cells and increased S100B secretion in vitro and in vivo in the presence of the S100B polymorphism. These findings point to a relevant role of the danger sensing signaling in human antifungal immunity and highlight a possible contribution of a genetically-determined hyperfunction of the S100B/RAGE axis to susceptibility to IA in the HSCT setting

Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis

Foxp3+ regulatory T cells (Treg cells) modulate the immune system and maintain self-tolerance, but whether they affect haematopoiesis or haematopoietic stem cell (HSC)-mediated reconstitution after transplantation is unclear. Here we show that B-cell lymphopoiesis is impaired in Treg-depleted mice, yet this reduced B-cell lymphopoiesis is rescued by adoptive transfer of affected HSCs or bone marrow cells into Treg-competent recipients. B-cell reconstitution is abrogated in both syngeneic and allogeneic transplantation using Treg-depleted mice as recipients. Treg cells can control physiological IL-7 production that is indispensable for normal B-cell lymphopoiesis and is mainly sustained by a subpopulation of ICAM1+ perivascular stromal cells. Our study demonstrates that Treg cells are important for B-cell differentiation from HSCs by maintaining immunological homoeostasis in the bone marrow microenvironment, both in physiological conditions and after bone marrow transplantation

Search for vector-like T quarks decaying to top quarks and Higgs bosons in the all-hadronic channel using jet substructure

Peer reviewe

Search for the production of dark matter in association with top-quark pairs in the single-lepton final state in proton-proton collisions at √s=8 TeV

Peer reviewe

Angular analysis of the decay B-0 -> K*(0)mu(+)mu(-) from pp collisions at root s=8 TeV

Peer reviewe

Search for a charged Higgs boson in pp collisions at root s=8 TeV

Peer reviewe