64 research outputs found
JAML immunotherapy targets recently activated tumor-infiltrating CD8+ T cells
No full textSummary: Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly restricted to and highly expressed by tissue-resident memory CD8+ T cells in multiple cancer types. By delineating the key cellular targets and functional consequences of agonistic anti-JAML therapy in a murine melanoma model, we show its specific mode of action and the reason for its synergistic effects with anti-PD-1
Imbalance of regulatory and cytotoxic SARS-CoV-2-Reactive CD4+ T cells in COVID-19
No full textThe contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (TH)1 cells and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4+ T cells in distinct disease severities
Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.
No full textPhosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity
Dataset For The `Performance Of The Eudet-Type Beam Telescopes' Publication (Epj Ti)
No full textThis repository holds the data on which the publication `Performance of the EUDET-type beam telescopes' is based on. The substructure is as follows: Files in the range of run000060.raw until run000112.raw belong to a geometry with plane distance dz = 150 mm. Files in the range of run000114.raw until run000171.raw belong to a geometry with plane distance dz = 20 mm. A run corresponds to a doublet of beam energy and sensor threshold settings. The numbers are detailed in the README file
Scattering Studies with the DATURA Beam Telescope
No full textHigh-precision particle tracking devices allow for two-dimensional analyses of the material budget distribution of particle detectors and their periphery. In this contribution, the material budget of different targets is reconstructed from the width of the angular distribution of scattered beam particle at a sample under test. Positrons in the GeV-range serve as beam particles carrying enough momentum to traverse few millimetre thick targets whilst offering sufficient deflection for precise measurement. Reference measurements of the scattering angle distribution of targets of known thicknesses are presented that serve as calibration techniques required for tomographic reconstructions of inhomogeneous objects.High-precision particle tracking devices allow for two-dimensional analyses of the material budget distribution of particle detectors and their periphery. In this contribution, the material budget of different targets is reconstructed from the width of the angular distribution of scattered beam particle at a sample under test. Electrons in the GeV-range serve as beam particles carrying enough momentum to traverse few millimetre thick targets whilst offering sufficient deflection for precise measurement. Reference measurements of the scattering angle distribution of targets of known thicknesses are presented that serve as calibration techniques required for tomographic reconstructions of inhomogeneous objects
Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy
No full textImmune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (TFR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy
EUTelescope : A modular reconstruction framework for beam telescope data
No full textEUTelescope is a modular, comprehensive software framework for the reconstruction of particle trajectories recorded with beam telescopes. Its modularity allows for a flexible usage of processors each fulfilling separate tasks of the reconstruction chain such as clustering, alignment and track fitting. The framework facilitates the usage of any position sensitive device for both the beam telescope sensors as well as the device under test and supports a wide range of geometric arrangements of the sensors. In this work, the functionality of the EUTelescope framework as released in v2.2 and its underlying dependencies are discussed. Various use cases with emphasis on the General Broken Lines advanced track fitting methods give examples of the work flow and capabilities of the framework
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