Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Acoustic Emission bei der Maschinen- und Prozesssüberwachung - Neue Analysemethoden und Anwendungsgebiete

"Measure what is measurable, and make measurable what is not so" this quote, which is attributed to the Italian scholar Galileo Galilei, illustrates the exceptional position of the measurement technology in the engineering disciplines. The visualization of technical or natural processes and the associated measuring of physical quantities is the driving force for understanding our environment. Today engineers are able to use a variety of measuring principles for the description of technical processes. Therefore the choice and the question of suitable sensor technology is becoming more and more complex.The present thesis extends this question to the consideration of acoustic emission technology. Thanks to advances in digital data processing and the development of high-performance measurement systems, acoustic emission measurement technology has increasingly become the focus of scientific as well as industrial applications. Due to the variety of possible applications it can be shown that this technology bears much potential and that the development of algorithms in order to process acoustic emission signals must be tailored for each application. In this work, three basic approaches for the analysis of acoustic emission signals are presented: statistical analysis in the time domain, frequency-based analysis, burst detection and subsequent waveform-based analysis. The complexity of the algorithms and thus the effort of the calculation and evaluation of acoustic emission signals is immense due to the high sampling rates and the huge amount of data. Particularly – in the case of burst detection and subsequent waveform-based analysis – it is necessary to enable fast and efficient data processing algorithms. There are three new burst detection methods presented which outperform the previous state of the art in efficiency and recognition quality. The waveform-based characteristics were extended by additional parameters in the time and frequency domain. Based on these parameters multiple burst-specific characteristics can be derived. The developed burst detector software enables a simple summary and evaluation of burst detection methods and parameters. This offers the potential for continued development, adapting old and implementation of new characteristics. In addition to the signal analysis the damping and dispersal behavior of acoustic emission signals is discussed in the present work. Furthermore, a mathematical and a metrological derivation of wave propagation and wave forms is presented. Based on four applications (material recognition during rock cutting, material flow and single grain characterization of calcium sulfate raw materials, crack initiation and crack growth using the example of endurance tests and machine diagnostics using the example of the monitoring of oscillating bearings) this thesis evaluates whether the acoustic emission technology is suitable for the generation additional of information about the technical process. This information can be used to automate processes and for monitoring the condition of materials and equipment.Furthermore, a measurement system is presented, which can be used for different applications. With the help of this measurement system Acoustic Emission measurement results can be visualized online and recommendations regarding machine and process control are derived based on the combination of multiple parameters. Based on this measurement system an offline analysis is no longer required and a quick control of processes (e.g. material detection during the cutting and material flow characterization) and a timely warning of a progressing damage (e.g. crack growth in components and bearing diagnosis) is possible