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8 results on '"Koster, Johannes"'

1. Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy

Author

Such, Lina, Zhao, Fang, Liu, Derek, Thier, Beatrice, Le-Trilling, Vu Thuy Khanh, Sucker, Antje, Coch, Christoph, Pieper, Natalia, Howe, Sebastian, Bhat, Hilal, Kalkavan, Halime, Ritter, Cathrin, Brinkhaus, Robin, Ugurel, Selma, Koster, Johannes, Seifert, Ulrike, Dittmer, Ulf, Schuler, Martin, Lang, Karl S., Kufer, Thomas A., Hartmann, Gunther, Becker, Jurgen C., Horn, Susanne, Ferrone, Soldano, Liu, David, Van Allen, Eliezer M., Schadendorf, Dirk, Griewank, Klaus, Trilling, Mirko, and Paschen, Annette

Subjects
Bristol-Myers Squibb Co., Novartis AG, Development and progression, Personal narratives, Antigens -- Personal narratives, Biological response modifiers -- Personal narratives, Medical research -- Personal narratives, Immunotherapy -- Personal narratives, Interferon -- Personal narratives, Melanoma -- Development and progression, RNA -- Personal narratives, T cells -- Personal narratives
Abstract

Introduction Cytotoxic [CD8.sup.+] T cells are critical mediators of clinical responses in tumor immunotherapy, killing cancer cells upon recognition of HLA class I (HLA-I) tumor antigen peptide complexes. Antigen processing [...], Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous [CD8.sup.+] T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription, thereby overcoming T cell resistance. Antigen presentation was restored in interferon-sensitive (IFN-sensitive) but also immunoedited IFN-resistant melanoma models through RIG-I-dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-[I.sup.hi] ([DDX58.sup.hi]) melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the antitumor T cell activity of ICB nonresponders. Overall, the herein-identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy.

Published
2020
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2. Accurate and scalable variant calling from single cell DNA sequencing data with ProSolo

Author

Lahnemann, David, Koster, Johannes, Fischer, Ute, Borkhardt, Arndt, McHardy, Alice C, Schönhuth, Alexander, and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.

Subjects
Statistical methods, Science, Tumour heterogeneity, Medizin, High-Throughput Nucleotide Sequencing, Genomics, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Article, 660.6, Genetic Techniques, Mutation, Humans, DNA sequencing, Single-Cell Analysis, Medical genomics, Software
Abstract

Accurate single cell mutational profiles can reveal genomic cell-to-cell heterogeneity. However, sequencing libraries suitable for genotyping require whole genome amplification, which introduces allelic bias and copy errors. The resulting data violates assumptions of variant callers developed for bulk sequencing. Thus, only dedicated models accounting for amplification bias and errors can provide accurate calls. We present ProSolo for calling single nucleotide variants from multiple displacement amplified (MDA) single cell DNA sequencing data. ProSolo probabilistically models a single cell jointly with a bulk sequencing sample and integrates all relevant MDA biases in a site-specific and scalable—because computationally efficient—manner. This achieves a higher accuracy in calling and genotyping single nucleotide variants in single cells in comparison to state-of-the-art tools and supports imputation of insufficiently covered genotypes, when downstream tools cannot handle missing data. Moreover, ProSolo implements the first approach to control the false discovery rate reliably and flexibly. ProSolo is implemented in an extendable framework, with code and usage at: https://github.com/prosolo/prosolo, Obtaining accurate variant calls from multiple displacement amplified single cell DNA sequencing data needs dedicated models that account for amplification bias and copy errors. Here, the authors describe ProSolo, a model for calling single nucleotide variants with control over the false discovery rate.

Published
2021
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4. Worldview-philosophy-through-film: an account of cognitive discomfiture in viewer-engagement

Author

Koster, Johannes Marthinus, Olivier, Bert, Koster, Johannes Marthinus, and Olivier, Bert

Abstract

The philosophy of painful art has a lineage that goes back at least as far as Aristotle's treatment of tragedy. Since the 1990s, the problem of cognitively confusing, negatively valenced film-viewing experiences has achieved a renewed significance because of the flourishing of the puzzle film and its unresolvable variant, the impossible puzzle film. This trend, which has unfolded within the emergence of mass art films and a mass cinephilia that have popularised the techniques of art and avant-garde cinema, may be best embodied in the films of David Lynch and specifically in his early masterwork, Twin Peaks: Fire Walk with Me (1992), a disorienting tale of incestuous sexual abuse. To investigate this topic, I adopt the piecemeal, mid-level approach that Noël Carroll has established within the broader research programme of cognitive (biocultural) film theory. Accordingly, I construct a rich-disclosure framework that accounts for cognitive discomfiture film-viewing experiences from well-founded, constructive explanatory material within film theory and the philosophy of film, and interdisciplinary support from social scientific research in media psychology. The most important of these sources are David Bordwell's neo-formalist model of conventional and unconventional cinema; Todd Berliner's reappreciation of the challenging dimensions of mainstream film; Torben Grodal's PEMCA flow/freeze model of viewer-engagement plus the saturationacceptance and upstream intentional access that it encompasses; Noël Carroll's dramaof-disclosure and erotetic, criterial prefocusing; and Aaron Smuts' integrative, nonhedonic theory of rich, value-constitutive film-viewing. The latter two sources contribute a further five important elements to the integrative cognitive-emotive model of viewerengagement, namely folk psychology, asymmetrical, 'twofolded' character engagement, negatively valenced affects, maieutically guided moral involvement, and narrative practice with therapeutic potential.

Published
2020

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