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Biology subjects

Lohneis, P.

Publications and source records attributed to Lohneis, P..

2 recordsLinked to original sources

Predicting the HER2 status in esophageal cancer from tissue microarrays using convolutional neural networks

BackgroundFast and accurate diagnostics are key for personalized medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies which can prolong lives. In this work we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalized therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep learning method for scoring microscopy images of GEA for the presence of HER2 overexpression. MethodsOur method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1,602 patient samples and tested on an independent set of 307 patient samples. We incorporated an attention mechanism in the CNN architecture to identify the tissue regions in these patient cases which the network has detected as important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridization (ISH) tests. ResultsWe show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve, requiring additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical center. ConclusionsWe demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.

bioinformatics↗

ATM-mediated DNA damage response in macrophages primes phagocytosis and immune checkpoint regulation

Genotoxin-based cancer therapies trigger a DNA damage response (DDR) to eliminate cancer cells but similarly exert profound alterations to the immune cell compartment. Macrophages in the tumor microenvironment are important and multifaceted components in actively sustaining tumor progression but also in clearance of tumor cells and play an important role in the outcome of chemotherapy. Here, we report that post neo-adjuvant chemotherapy macrophages in tumor samples display elevated expression of the immune checkpoint PD-L1. We determined that chemotherapy or direct application of DNA damage to macrophages in vitro triggers a specific MDDR polarization phenotype characterized by increased phagocytic activity, elevated PD-L1 expression, and induction of endotoxin tolerance. Phospho-proteomics analysis revealed epigenetic alterations and ATM-dependent induction of senescence in macrophages upon DNA damage. We propose that ATM-induced senescence and PD-L1 immune checkpoint induction mediate a specific MDDR macrophage polarization that might contribute to chemotherapy responses. Furthermore, our results clarify the functional role of tumor associated macrophages in the context of DNA damage and combination therapies including checkpoint inhibition.

immunology↗